This is a very complex subject, so as usual I will try to stick to the essentials to make things as clear as possible, while details can be dealt with in the discussion.
It is difficult to define exactly the role of the Ubiquitin System. It is usually considered mainly a pathway which regulates protein degradation, but in reality its functions are much wider than that.
In essence, the US is a complex biological system which targets many different types of proteins for different final fates.
The most common “fate” is degradation of the protein. In that sense, the Ubiquitin System works together with another extremely complex cellular system, the proteasome. In brief, the Ubiquitin System “marks” proteins for degradation, and the proteasome degrades them.
It seems simple. It is not.
Ubiquitination is essentially one of many Post-Translational modifications (PTMs): modifications of proteins after their synthesis by the ribosome (translation). But, while most PTMs use simpler biochemical groups that are usually added to the target protein (for example, acetylation), in ubiquitination a whole protein (ubiquitin) is used as a modifier of the target protein.
The tool: Ubiquitin
Ubiquitin is a small protein (76 AAs). Its name derives from the simple fact that it is found in most tissues of eukaryotic organisms.
Here is its aminoacid sequence:
MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPD
QQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG
Essentially, it has two important properties:
- As said, it is ubiquitous in eukaryotes
- It is also extremely conserved in eukaryotes
In mammals, ubiquitin is not present as a single gene. It is encoded by 4 different genes: UBB, a poliubiquitin (3 Ub sequences); UBC, a poliubiquitin (9 Ub sequences); UBA52, a mixed gene (1 Ub sequence + the ribosomal protein L40); and RPS27A, again a mixed gene (1 Ub sequence + the ribosomal protein S27A). However, the basic ubiquitin sequence is always the same in all those genes.
Its conservation is one of the highest in eukaryotes. The human sequence shows, in single celled eukaryotes:
Naegleria: 96% conservation; Alveolata: 100% conservation; Cellular slime molds: 99% conservation; Green algae: 100% conservation; Fungi: best hit 100% conservation (96% in yeast).
Ubiquitin and Ubiquitin like proteins (see later) are characterized by a special fold, called β-grasp fold.
The semiosis: the ubiquitin code
The title of this OP makes explicit reference to semiosis. Let’s try to see why.
The simplest way to say it is: ubiquitin is a tag. The addition of ubiquitin to a substrate protein marks that protein for specific fates, the most common being degradation by the proteasome.
But not only that. See, for example, the following review:
Nonproteolytic Functions of Ubiquitin in Cell Signaling
Abstract:
The small protein ubiquitin is a central regulator of a cell’s life and death. Ubiquitin is best known for targeting protein destruction by the 26S proteasome. In the past few years, however, nonproteolytic functions of ubiquitin have been uncovered at a rapid pace. These functions include membrane trafficking, protein kinase activation, DNA repair, and chromatin dynamics. A common mechanism underlying these functions is that ubiquitin, or polyubiquitin chains, serves as a signal to recruit proteins harboring ubiquitin-binding domains, thereby bringing together ubiquitinated proteins and ubiquitin receptors to execute specific biological functions. Recent advances in understanding ubiquitination in protein kinase activation and DNA repair are discussed to illustrate the nonproteolytic functions of ubiquitin in cell signaling.
Another important aspect is that ubiquitin is not one tag, but rather a collection of different tags. IOWs, a tag based code.
See, for example, here:
The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy
(Paywall).
Abstract:
The conjugation of the 76 amino acid protein ubiquitin to other proteins can alter the metabolic stability or non-proteolytic functions of the substrate. Once attached to a substrate (monoubiquitination), ubiquitin can itself be ubiquitinated on any of its seven lysine (Lys) residues or its N-terminal methionine (Met1). A single ubiquitin polymer may contain mixed linkages and/or two or more branches. In addition, ubiquitin can be conjugated with ubiquitin-like modifiers such as SUMO or small molecules such as phosphate. The diverse ways to assemble ubiquitin chains provide countless means to modulate biological processes. We overview here the complexity of the ubiquitin code, with an emphasis on the emerging role of linkage-specific degradation signals (degrons) in the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (hereafter autophagy).
A good review of the basics of the ubiquitin code can be found here:
(Paywall)
It is particularly relevant, from an ID point of view, to quote the starting paragraph of that paper:
When in 1532 Spanish conquistadores set foot on the Inca Empire, they found a highly organized society that did not utilize a system of writing. Instead, the Incas recorded tax payments or mythology with quipus, devices in which pieces of thread were connected through specific knots. Although the quipus have not been fully deciphered, it is thought that the knots between threads encode most of the quipus’ content. Intriguingly, cells use a regulatory mechanism—ubiquitylation—that is reminiscent of quipus: During this reaction, proteins are modified with polymeric chains in which the linkage between ubiquitin molecules encodes information about the substrate’s fate in the cell.
Now, ubiquitin is usually linked to the target protein in chains. The first ubiquitin molecule is covalently bound through its C-terminal carboxylate group to a particular lysine, cysteine, serine, threonine or N-terminus of the target protein.
Then, additional ubiquitins are added to form a chain, and the C-terminus of the new ubiquitin is linked to one of seven lysine residues or the first methionine residue on the previously added ubiquitin.
IOWs, each ubiquitin molecule has seven lysine residues:
K6, K11, K27, K29, K33, K48, K63
And one N terminal methionine residue:
M1
And a new ubiquitin molecule can be added at each of those 8 sites in the previous ubiquitin molecule. IOWs, those 8 sites in the molecule are configurable switches that can be used to build ubiquitin chains.
Her are the 8 sites, in red, in the ubiquitin molecule:
MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPD
QQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG
Fig 1 shows two ubiquitin molecules joined at K48.
The simplest type of chain is homogeneous (IOWs, ubiquitins are linked always at the same site). But many types of mixed and branched chains can also be found.
Let’s start with the most common situation: a poli-ubiquitination of (at least) 4 ubiqutins, linearly linked at K48. This is the common signal for proteasome degradation.
By the way, the 26S proteasome is another molecular machine of incredible complexity, made of more than 30 different proteins. However, its structure and function are not the object of this OP, and therefore I will not deal with them here.
The ubiquitin code is not completely understood, at present, but a few aspects have been well elucidated. Table 1 sums up the most important and well known modes:
Code |
Meaning |
| Polyubiquitination (4 or more) with links at K48 or at K11 | Proteasomal degradation |
| Monoubiqutination (single or multiple) | Protein interactions, membrane trafficking, endocytosis |
| Polyubiquitination with links at K63 | Endocytic trafficking, inflammation, translation, DNA repair. |
| Polyubiquitination with links at K63 (other links) | Autophagic degradation of protein substrates |
| Polyubiquitination with links at K27, K29, K33 | Non proteolytic processes |
| Rarer chain types (K6, K11) | Under investigation |
However, this is only a very partial approach. A recent bioinformatics paper:
An Interaction Landscape of Ubiquitin Signaling
(Paywall)
Has attempted for the first time a systematic approach to deciphering the whole code, using synthetic diubiquitins (all 8 possible variants) to identify the different interactors with those signals, and they identified, with two different methodologies, 111 and 53 selective interactors for linear polyUb chains, respectively. 46 of those interactors were identified by both methodologies.
The translation
But what “translates” the complex ubiquitin code, allowing ubiquinated proteins to met the right specific destiny? Again, we can refer to the diubiquitin paper quoted above.
How do cells decode this ubiquitin code into proper cellular responses? Recent studies have indicated that members of a protein family, ubiquitin-binding proteins (UBPs), mediate the recognition of ubiquitinated substrates. UBPs contain at least one of 20 ubiquitin-binding domains (UBDs) functioning as a signal adaptor to transmit the signal from ubiquitinated substrates to downstream effectors
But what are those “interactors” identified by the paper (at least 46 of them)? They are, indeed, complex proteins which recognize specific configurations of the “tag” (the ubiquitin chain), and link the tagged (ubiquinated) protein to other effector proteins which implement its final fate, or anyway contribute in deffrent forms to that final outcome.
The basic control of the procedure: the complexity of the ubiquitination process.
So, we have seen that ubiquitin chains work as tags, and that their coded signals are translated by specific interactors, so that the target protein may be linked to its final destiny, or contribute to the desired outcome. But we must still address one question: how is the ubiquitination of the different target proteins implemented? IOWs, what is the procedure that “writes” the specific codes associated to specific target proteins?
This is indeed the first step in the whole process. But it is also the most complex, and that’s why I have left it for the final part of the discussion.
Indeed, the ubiquitination process needs to realize the following aims:
- Identify the specific protein to be ubiquitinated
- Recognize the specific context in which that protein needs to be ubiquitinated
- Mark the target protein with the correct tag for the required fate or outcome
We have already seen that the ubiquitin system is involved in practically all different cellular paths and activities, and therefore we can expect that the implementation of the above functions must be a very complex thing.
And it is.
Now, we can certainly imagine that there are many different layers of regulation that may contribute to the general control of the procedure, specifically epigenetic levels, which are at present poorly understood. But there is one level that we can more easily explore and understand, and it is , as usual, the functional complexity of the proteins involved.
And, even at a first gross analysis, it is really easy to see that the functional complexity implied by this process is mind blowing.
Why? It is more than enough to consider the huge number of different proteins involved. Let’s see.
The ubiquitination process is well studied. It can be divided into three phases, each of which is implemented by a different kind of protein. The three steps, and the three kinds of proteins that implement them, take the name of E1, E2 and E3.
The E1 step of ubiquitination.
This is the first thing that happens, and it is also the simplest.
E1 is the process of activation of ubiquitin, and the E1 proteins is called E1 ubiquitin-activating enzyme. To put it simply, this enzyme “activates” the ubiquitin molecule in an ATP dependent process, preparing it for the following phases and attaching it to its active site cysteine residue. It is not really so simple, but for our purposes that can be enough.
This is a rather straightforward enzymatic reaction. In humans there are essentially two forms of E1 enzymes, UBA1 and UBA6, each of them about 1000 AAs long, and partially related at sequence level (42%).
The E2 step of ubiquitination.
The second step is ubiquitin conjugation. The activated ubiquitin is transferred from the E1 enzyme to the ubiquitin-conjugating enzyme, or E2 enzyme, where it is attached to a cysteine residue.
This apparently simple “transfer” is indeed a complex intermediate phase. Humans have about 40 different E2 molecules. The following paper:
E2 enzymes: more than just middle men
details some of the functional complexity existing at this level.
Abstract:
Ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins. Humans have ∼40 E2s that are involved in the transfer of Ub or Ub-like (Ubl) proteins (e.g., SUMO and NEDD8). Although the majority of E2s are only twice the size of Ub, this remarkable family of enzymes performs a variety of functional roles. In this review, we summarize common functional and structural features that define unifying themes among E2s and highlight emerging concepts in the mechanism and regulation of E2s.
However, I will not go into details about these aspects, because we have better things to do: we still have to discuss the E3 phase!
The E3 step of ubiquitination.
This is the last phase of ubiquitination, where the ubiquitin tag is finally transferred to the target protein, as initial mono-ubiquitination, or to build an ubiquitin chain by following ubiqutination events. The proteins which implement this final passage are call E3 ubiquitin ligases. Here is the definition from Wikipedia:
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate.
It is rather obvious that the role of the E3 protein is very important and delicate. Indeed it:
- Recognizes and links the E2-ubiquitin complex
- Recognizes and links some specific target protein
- Builds the appropriate tag for that protein (Monoubiquitination, mulptiple monoubiquitination, or poliubiquitination with the appropriate type of ubiquitin chain).
- And it does all those things at the right moment, in the right context, and for the right protein.
IOWs, the E3 protein writes the coded tag. It is, by all means, the central actor in our complex story.
So, here comes the really important point: how many different E3 ubiquitin ligases do we find in eukaryotic organisms? And the simple answer is: quite a lot!
Humans are supposed to have more than 600 different E3 ubiquitin ligases!
So, the human machinery for ubiquitination is about:
2 E1 proteins – 40 E2 proteins – >600 E3 proteins
A real cascade of complexity!
OK, but even if we look at single celled eukaryotes we can already find an amazing level of complexity. In yeast, for example, we have:
1 or 2 E1 proteins – 11 E2 proteins – 60-100 E3 proteins
See here:
The Ubiquitin–Proteasome System of Saccharomyces cerevisiae
Now, a very important point. Those 600+ E3 proteins that we find in humans are really different proteins. Of course, they have something in common: a specific domain.
From that point of view, they can be roughly classified in three groups according to the specific E3 domain:
- RING group: the RING finger domain ((Really Interesting New Gene) is a short domain of zinc finger type, usually 40 to 60 amino acids. This is the biggest group of E3s (about 600)
- HECT domain (homologous to the E6AP carboxyl terminus): this is a bigger domain (about 350 AAs). Located at the C terminus of the protein. It has a specific ligase activity, different from the RING In humans we have approximately 30 proteins of this type.
- RBR domain (ring between ring fingers): this is a common domain (about 150 AAs) where two RING fingers are separated by a region called IBR, a cysteine-rich zinc finger. Only a subset of these proteins are E3 ligases, in humans we have about 12 of them.
See also here.
OK, so these proteins have one of these three domains in common, usually the RING domain. The function of the domain is specifically to interact with the E2-ubiquitin complex to implement the ligase activity. But the domain is only a part of the molecule, indeed a small part of it. E3 ligases are usually big proteins (hundreds, and up to thousands of AAs). Each of these proteins has a very specific non domain sequence, which is probably responsible for the most important part of the function: the recognition of the specific proteins that each E3 ligase processes.
This is a huge complexity, in terms of functional information at sequence level.
Our map of the ubiquinating system in humans could now be summarized as follows:
2 E1 proteins – 40 E2 proteins – 600+ E3 proteins + thousands of specific substrates
IOWs, each of hundreds of different complex proteins recognizes its specific substrates, and marks them with a shared symbolic code based on uniquitin and its many possible chains. And the result of that process is that proteins are destined to degradation by the proteasome or other mechanisms, and that protein interactions and protein signaling are regulated and made possible, and that practically all cellular functions are allowed to flow correctly and smoothly.
Finally, here are two further compoments of the ubuquitination system, which I will barely mention, to avoid making this OP too long.
Ubiquitin like proteins (Ubl):
A number of ubiquitin like proteins add to the complexity of the system. Here is the abstract from a review:
The eukaryotic ubiquitin family encompasses nearly 20 proteins that are involved in the posttranslational modification of various macromolecules. The ubiquitin-like proteins (UBLs) that are part of this family adopt the β-grasp fold that is characteristic of its founding member ubiquitin (Ub). Although structurally related, UBLs regulate a strikingly diverse set of cellular processes, including nuclear transport, proteolysis, translation, autophagy, and antiviral pathways. New UBL substrates continue to be identified and further expand the functional diversity of UBL pathways in cellular homeostasis and physiology. Here, we review recent findings on such novel substrates, mechanisms, and functions of UBLs.
These proteins include SUMO, Nedd8, ISB15, and many others.
Deubiquitinating enzymes (DUBs):
The process of ubiquitination, complex as it already is, is additionally regulated by these enzymes which can cleave ubiquitin from proteins and other molecules. Doing so, they can reverse the effects of ubiquitination, creating a delicately balanced regulatory network. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases.
By the way, here is a beautiful animation of the basic working of the ubiquitin-proteasome system in degrading damaged proteins:
A summary:
So, let’s try a final graphic summary of the whole ubiquitin system in humans:
Evolution of the Ubiquitin system?
The Ubiqutin system is essentially an eukaryotic tool. Of course, distant precursors for some of the main components have been “found” in prokaryotes. Here is the abstract from a paper that sums up what is known about the prokaryotic “origins” of the system:
Structure and evolution of ubiquitin and ubiquitin-related domains.
(Paywall)
Abstract:
Since its discovery over three decades ago, it has become abundantly clear that the ubiquitin (Ub) system is a quintessential feature of all aspects of eukaryotic biology. At the heart of the system lies the conjugation and deconjugation of Ub and Ub-like (Ubls) proteins to proteins or lipids drastically altering the biochemistry of the targeted molecules. In particular, it represents the primary mechanism by which protein stability is regulated in eukaryotes. Ub/Ubls are typified by the β-grasp fold (β-GF) that has additionally been recruited for a strikingly diverse range of biochemical functions. These include catalytic roles (e.g., NUDIX phosphohydrolases), scaffolding of iron-sulfur clusters, binding of RNA and other biomolecules such as co-factors, sulfur transfer in biosynthesis of diverse metabolites, and as mediators of key protein-protein interactions in practically every conceivable cellular context. In this chapter, we present a synthetic overview of the structure, evolution, and natural classification of Ub, Ubls, and other members of the β-GF. The β-GF appears to have differentiated into at least seven clades by the time of the last universal common ancestor of all extant organisms, encompassing much of the structural diversity observed in extant versions. The β-GF appears to have first emerged in the context of translation-related RNA-interactions and subsequently exploded to occupy various functional niches. Most biochemical diversification of the fold occurred in prokaryotes, with the eukaryotic phase of its evolution mainly marked by the expansion of the Ubl clade of the β-GF. Consequently, at least 70 distinct Ubl families are distributed across eukaryotes, of which nearly 20 families were already present in the eukaryotic common ancestor. These included multiple protein and one lipid conjugated forms and versions that functions as adapter domains in multimodule polypeptides. The early diversification of the Ubl families in eukaryotes played a major role in the emergence of characteristic eukaryotic cellular substructures and systems pertaining to nucleo-cytoplasmic compartmentalization, vesicular trafficking, lysosomal targeting, protein processing in the endoplasmic reticulum, and chromatin dynamics. Recent results from comparative genomics indicate that precursors of the eukaryotic Ub-system were already present in prokaryotes. The most basic versions are those combining an Ubl and an E1-like enzyme involved in metabolic pathways related to metallopterin, thiamine, cysteine, siderophore and perhaps modified base biosynthesis. Some of these versions also appear to have given rise to simple protein-tagging systems such as Sampylation in archaea and Urmylation in eukaryotes. However, other prokaryotic systems with Ubls of the YukD and other families, including one very close to Ub itself, developed additional elements that more closely resemble the eukaryotic state in possessing an E2, a RING-type E3, or both of these components. Additionally, prokaryotes have evolved conjugation systems that are independent of Ub ligases, such as the Pup system.
As usual, we are dealing here with distant similarities, but there is no doubt that the ubiquitin system as we know it appears in eukaryotes.
But what about its evolutionary history in eukaryotes?
We have already mentioned the extremely high conservation of ubiquitin itself.
UBA1, the main E1 enzyme, is rather well conserved from fungi to humans: 60% identity, 1282 bits, 1.21 bits per aminoacid (baa).
E2s are small enzymes, extremely conserved from fungi to humans: 86% identity, for example, for UB2D2, a 147 AAs molecule.
E3s, of course, are the most interesting issue. This big family of proteins behaves in different ways, consistently with its highly specific functions.
It is difficult to build a complete list of E3 proteins. I have downloaded from Uniprot a list of reviewed human proteins including “E3 ubiquitun ligase” in their name: a total of 223 proteins.
The mean evolutionary behavior of this group in metazoa is rather different from protein to protein. However, as a group these proteins exhibit an information jump in vertebrates which is significantly higher than the jump in all other proteins:
As we already know, this is evidence that this class of proteins is highly engineered in the transition to vertebrates. That is consistent with the need to finely regulate many cellular processes, most of which are certainly highly specific for different groups of organisms.
The highest vertebrate jump, in terms of bits per aminoacid, is shown in my group by the E3 ligase TRIM62. also known as DEAR1 (Q9BVG3), a 475 AAs long protein almost absent in pre-vertebrates (best hit 129 bits, 0.27 baa in Branchiostoma belcheri) and which flaunts an amazing jump of 1.433684 baa in cartilaginous fish (810 bits, 1.705263 baa).
But what is this protein? It is a master regulator tumor suppressor gene, implied in immunity, inflammation, tumor genesis.
See here:
and here:
This is just to show what a single E3 ligase can be involved in!
An opposite example, from the point of view of evolutionary history, is SIAH1, an E3 ligase implied in proteosomal degradation of proteins. It is a 282 AAs long protein, which already exhibits 1.787234 baa (504 bits) of homology in deuterostomes, indeed already 1.719858 baa in cnidaria. However, in fungi the best hit is only 50.8 bits (0.18 baa). So, this is a protein whose engineering takes place at the start of metazoa, and which exhibits only a minor further jump in vertebrates (0.29 baa), which brings the protein practically to its human form already in cartilaginous fish (280 identities out of 282, 99%). Practically a record.
So, we can see that E3 ligases are a good example of a class of proteins which perform different specific functions, and therefore exhibit different evolutionary histories: some, like TRIM62, are vertebrate quasi-novelties, others, like SIAH1, are metazoan quasi-novelties. And, of course, there are other behaviours, like for example BRCA1, Breast cancer type 1 susceptibility protein, a protein 1863 AAs long which only in mammals acquires part of its final sequence configuration in humans.
The following figure shows the evolutionary history of the three proteins mentioned above.
An interesting example: NF-kB signaling
I will discuss briefly an example of how the Ubiquitin system interacts with some specific and complex final effector system. One of the best models for that is the NF-kB signaling.
NK-kB is a transcription factor family that is the final effector of a complex signaling pathway. I will rely mainly on the following recent free paper:
The Ubiquitination of NF-κB Subunits in the Control of Transcription
Here is the abstract:
Nuclear factor (NF)-κB has evolved as a latent, inducible family of transcription factors fundamental in the control of the inflammatory response. The transcription of hundreds of genes involved in inflammation and immune homeostasis require NF-κB, necessitating the need for its strict control. The inducible ubiquitination and proteasomal degradation of the cytoplasmic inhibitor of κB (IκB) proteins promotes the nuclear translocation and transcriptional activity of NF-κB. More recently, an additional role for ubiquitination in the regulation of NF-κB activity has been identified. In this case, the ubiquitination and degradation of the NF-κB subunits themselves plays a critical role in the termination of NF-κB activity and the associated transcriptional response. While there is still much to discover, a number of NF-κB ubiquitin ligases and deubiquitinases have now been identified which coordinate to regulate the NF-κB transcriptional response. This review will focus the regulation of NF-κB subunits by ubiquitination, the key regulatory components and their impact on NF-κB directed transcription.
The following figure sums up the main features of the canonical activation pathway:
Here the NF-κB TF is essentially the heterodimer RelA – p50. Before activation, the NF-κB (RelA – p50) dimer is kept in an inactive state and remains in the cytoplasm because it is linked to the IkB alpha protein, an inhibitor of its function.
Activation is mediated by a signal-receptor interaction, which starts the whole pathway. A lot of different signals can do that, adding to the complexity, but we will not discuss this part here.
As a consequence of receptor activation, another protein complex, IκB kinase (IKK), accomplishes the Phosphorylation of IκBα at serines 32 and 36. This is the signal for the ubiquitination of the IkB alpha inhibitor.
This ubiqutination targets IkB alpha for proteosomal degradation. But how is it achieved?
Well, things are not so simple. A whole protein complex is necessary, a complex which implements many different ubiquitinations in different contexts, including this one.
The complex is made by 3 basic proteins:
- Cul1 (a scaffold protein, 776 AAs)
- SKP1 (an adaptor protein, 163 AAs)
- Rbx1 (a RING finger protein with E3 ligase activity, 108 AAs)
Plus:
- An F-box protein (FBP) which changes in the different context, and confers specificity.
In our context, the F box protein is called beta TRC (605 AAs).
Once the IkB alpha inhibitor is ubiquinated and degraded in the proteasome, the NF-κB dimer is free to translocate to the nucleus, and implement its function as a transcription factor (which is another complex issue, that we will not discuss).
OK, this is only the canonical activation of the pathway.
In the non canonical pathway (not shown in the figure) a different set of signals, receptors and activators acts on a different NF-κB dimer (RelB – p100). This dimer is not linked to any inhibitor, but is itself inactive in the cytoplasm. As a result of the signal, p100 is phosphorylated at serines 866 and 870. Again, this is the signal for ubiquitination.
This ubiquitination is performed by the same complex described above, but the result is different. P100 is only partially degraded in the proteasome, and is transformed into a smaller protein, p52, which remains linked to RelB. The RelB – p52 dimer is now an active NF-κB Transcription Factor, and it can relocate to the nucleus and act there.
But that’s not all.
- You may remember that RelA (also called p 65) is one of the two components of NF-kB TF in the canonical pathway (the other being p 50). Well, RelA is heavily controlled by ubiquitination after it binds DNA in the nucleus to implement its TF activity. Ubiquitination (a very complex form of it) helps detachment of the TF from DNA, and its controlled degradation, avoiding sustained expression of NF-κB-dependent genes. For more details, see section 4 in the above quoted paper: “Ubiquitination of NF-κB”.
- The activation of IKK in both the canonical and non canonical pathway after signal – receptor interaction is not so simple as depicted in Fig. 6. For more details, look at Fig. 1 in this paper: Ubiquitin Signaling in the NF-κB Pathway. You can see that, in the canonical pathway, the activation of IKK is mediated by many proteins, including TRAF2, TRAF6, TAK1, NEMO.
- TRAF2 is a key regulator on many signaling pathways, including NF-kB. It is an E3 ubiquitin ligase. From Uniprot: “Has E3 ubiquitin-protein ligase activity and promotes ‘Lys-63’-linked ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases.”
- The same is true of TRAF6.
- NEMO (NF-kappa-B essential modulator ) is also a key regulator. It is not an ubiquinating enzyme, but it is rather heavily regulated by ubiquitination. From Uniprot: “Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Its binding to scaffolding polyubiquitin seems to play a role in IKK activation by multiple signaling receptor pathways. However, the specific type of polyubiquitin recognized upon cell stimulation (either ‘Lys-63’-linked or linear polyubiquitin) and its functional importance is reported conflictingly.”
- In the non canonical pathway, the activation of IKK alpha after signal – receptor interaction is mediated by other proteins, in particular one protein called NIK (see again Fig. 1 quoted above). Well, NIK is regulated by two different types of E3 ligases, with two different types of polyubiquitination:
- cIAP E3 ligase inactivates it by constant degradation using a K48 chain
- ZFP91 E3 ligase stabilizes it using a K63 chain
See here:
Non-canonical NF-κB signaling pathway.
In particular, Fig. 3
These are only some of the ways the ubiquitin system interacts with the very complex NF-kB signaling system. I hope that’s enough to show how two completely different and complex biological systems manage to cooperate by intricate multiple connections, and how the ubiquitin system can intervene at all levels of another process. What is true for the NF-kB signaling pathway is equally true for a lot of other biological systems, indeed for almost all basic cellular processes.
But this OP is already too long, and I have to stop here.
As usual, I want to close with a brief summary of the main points:
- The Ubiquitin system is a very important regulation network that shows two different signatures of design: amazing complexity and an articulated semiotic structure.
- The complexity is obvious at all levels of the network, but is especially amazing at the level of the hundreds of E3 ligases, that can recognize thousands of different substrates in different contexts.
- The semiosis is obvious in the Ubiquitin Code, a symbolic code of different ubiquitin configurations which serve as specific “tags” that point to different outcomes.
- The code is universally implemented and shared in eukaryotes, and allows control on almost all most important cellular processes.
- The code is written by the hundreds of E3 ligases. It is read by the many interactors with ubiquitin-binding domains (UBDs).
- The final outcome is of different types, including degradation, endocytosis, protein signaling, and so on.
- The interaction of the Ubiquitin System with other complex cellular pathways, like signaling pathways, is extremely complex and various, and happens at many different levels and by many different interacting proteins for each single pathway.
PS:
Thanks to DATCG for pointing to this video in three parts by Dr. Raymond Deshaies, was Professor of Biology at the California Institute of Technology and an Investigator of the Howard Hughes Medical Institute. On iBiology Youtube page:
A primer on the ubiquitin-proteasome system
Cullin-RING ubiquitin ligases: structure, structure, mechanism, and regulation
Targeting the ubiquitin-proteasome system in cancer
Oooooooooooooohhhh more fun 🙂
I need time to read later and look forward to another good discussion.
I made a quick comment on Spliceosome post by you and scientist Arthur Hunt’s disappearance from the discussion a moment ago.
Scientist Arthur Hunt: https://www.researchgate.net/profile/Arthur_Hunt
Thought he would contribute to a good debate and discussion points in opposition to you Gpuccio on the Spliceosome, it’s evolution, Design or not.
But he seems to have disappeared without any rebuttal to your detailed responses…
Spliceosome – Defy non-Design Explanations
.
DATCG:
Thank you for opening the discussion! 🙂
I understand that the OP is rather long and touches a lot of stuff. I hope that you and others who are interested in this kind of approach can give a very good contribution to a discussion about this fascinating issue.
Of course, UB is specially invited to comment: he is the master of the semiosis arguments, and I am sure that he will be interested in the things discussed here. 🙂
Like you, I have been a little disappointed of the apparent disappearance of Arthur Hunt from the spliceosome discussion. He could certainly have given a great contribution. However, not knowing his reasons, I cannot certainly judge.
Looking forward to it. Thanks again for your interesting post. And yes, very much like this approach. Hope others join in.
Nothing like peering through signals, interpretations and post-translations and meta layers of information code on top of code.
Conditional processing is a feature here I think as well as specificity.
Agree with you. Not judging Arthur. If my speculation is correct, then I’m defending him. And hope he may show up in the future.
But onward 🙂
To the Ubiquitin Code.
And hope it’s OK to add a video overview in 3 parts for those who might like to see some animation along with explanations.
By Dr. Raymond Deshaies, was Professor of Biology at the California Institute of Technology and an Investigator of the Howard Hughes Medical Institute. On iBiology Youtube page.
A primer on the ubiquitin-proteasome system…
https://www.youtube.com/watch?v=ILdEOXCfgUc
There’s more of course, but thought he added some good insights.
DATCG:
Thank you for the link to the video. I have added it (alll three parts) at the end of the OP. I have not yet had the time to see them all, but I will, and I will comment on the points I find most interesting! 🙂
Yes, codes are of supreme importance in cellular life, and they do scream design.
You say:
“Conditional processing is a feature here I think as well as specificity.”
That’s exactly the point! This ubiquitin code is a perfect implementation of conditional processing, an equivalent of complex “if – else” structures.
Using an universal tag with internal configurable switches is really a brilliant solution for that.
And it also reminds me of Lego construction toys! 🙂
DATCG:
At timepoint 2:39 of the first video there is already a very important point which deserves discussion: why proteins, and especially regulator proteins, need to be unstable so that adjustments in their steady state can be achieved quickly.
It means that biological systems invest a lot of resources to achieve flexibility and quick (and very intelligent) adaptation to changing conditions.
I suppose that can be achieved because one of life’s features is to depend so critically on far from equilibrium processes.
Food for thought.
DATCG:
At timepoint 23:25 of the first video there is a brief explanation of the role of phosphorylation in regulating ubiquitination.
I have given an example of that in the OP, when I speak of the regulation of NF-kB, where phosphorylation provides the ubiquitination activating signal, both in the canonical and non canonical pathway, acting on the substrate. As shown in the video, phosphorylarion can act both on the substrate and on the E3 ligase, and finally it can also have an inhibitory role.
This is fascinating, because we have a simpler semiotic system (phosphorylation) which controls a much more complex semiotic system (ubiquitination) to regulate the working of an effector system (NF-kB signaling) which is, itself, highly semiotic.
DATCG:
The second video is very interesting too. Starting at 1:33, the structure of Cal1 E3 ligases (of which the one shown at Fig. 7 in the OP is a very good example) seems to be a wonderful example of modular design.
70 F-boxes.
40 SOCS boxes.
250 different assemblies.
Really amazing!
gpuccio,
Excellent OP, as usual. Thanks.
Also very interesting discussion with DATCG, who writes insightful comments and pointed to an interesting biology video series on the same fascinating topic of the OP.
Here’s a link to a full text PDF copy of one of the papers you referenced in the OP:
https://www.researchgate.net/profile/Lakshminarayan_Iyer/publication/221848141_Structure_and_Evolution_of_Ubiquitin_and_Ubiquitin-Related_Domains/links/57436c4a08aea45ee84d1061/Structure-and-Evolution-of-Ubiquitin-and-Ubiquitin-Related-Domains.pdf
Note the 21 citations to the given paper.
PS, my current activities are keeping me from commenting lately. Perhaps that’s pleasant news to some folks out there who were annoyed by my posts and even kept statistical track of their frequency and volume, but never dared to address them seriously. What else is new?
The project I’ve been working on has proceeded to another phase that requires more attention to difficult for me issues.
Dionisio:
That will perhaps be pleasant news to some folks, but believe me, you will be missed by many others, including me.
I am happy that your project is proceeding. However, I hope that you can still find some time to be with us, maybe with less frequency and volume, but with your usual ingenuity! 🙂
I think that the title of the following 2016 paper about the ubiquitin system could be of some interest:
“Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807260/
(Emphasis mine. Public access.)
The Abstract is very interesting, too:
(Emphasis mine)
The theme of intrinsically disordered regions in proteins is becoming ever more relevant.
See also here:
“Classification of Intrinsically Disordered Regions and Proteins”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095912/
Public access.
I quote just the title of the first section:
1.1. Uncharacterized Protein Segments Are a Source of Functional Novelty
This is a funny video. She does not use Lego, but something like that…
https://www.youtube.com/watch?v=miZYmuDKO2s
About histone ubiquitination, which I have not touched in the OP, here is an interesting paper:
“Histone Ubiquitination and Deubiquitination in Transcription, DNA Damage Response, and Cancer”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355875/
(Public access)
Both monoubiquitination and polyubiquitination seem to happen at histone level.
About branched ubiquitin chains and, again, NF-kB regulation:
The K48-K63 Branched Ubiquitin Chain Regulates NF-kB Signaling.
http://www.cell.com/molecular-.....16)30563-9
(Public access)
Abstract:
I have added to the OP a beautiful animation of the ubiquitin-proteasome system in degrading damaged proteins.
In the OP I have barely mentioned the role of ubiquitination in DNA repair.
This is interestng, because ubiquitination acts mainly at the level of histones.
We know that Post Translational Modifications (PTMs) of histones are in themselves a code, the histone code. This code is, too, highly symbolic, and very complex indeed. See, for example, Wikipedia:
https://en.wikipedia.org/wiki/Histone_code
However, the histone code is mainly written by simpler PTMs, especially methylation (mono, di and tri methylation) and acetylation. The role of ubiquitin here is minor.
But in the case of DNA damage, especially Double-Strand Breaks (DSB), ubiquitin becomes the absolute protagonist, and directs the repair process in an extremely complex and detailed way. See, for example, this paper:
Writers, Readers, and Erasers of Histone Ubiquitylation in DNA Double-Strand Break Repair
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923129/
The main role seems to be played by two E3 ligases, RNF8 and RNF 168, but a lot of other proteins are involved.
So, this is another example of two complex symbolic codes (histone code and ubiquitin code) strongly interacting, in a highly dynamic and articulated pattern.
This is the most amazing thing I have ever heard.
butifnot:
There are a lot of highly amazing things in biology.
But we have to dig deep into them, to really understand and appreciate their complexity and value.
As in many other contexts, the devil is in the details! 🙂
And, of course, deubiquitinating enzymes have a key role in regulating DNA repair. See here:
Fine-tuning the ubiquitin code at DNA double-strand breaks: deubiquitinating enzymes at work
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561801/
If you love simplicity, just look at Figure 1! And carefully read the Figure legend… 🙂
gpuccio @16:
That’s an understatement. 🙂
gpuccio @17:
That figure 1 legend has material to fill post-doc course textbooks.
This thread has too much bad news for the ‘modern synthesis’ and the ‘third way’ clubs. 🙂
a deubiquitinating enzyme complex regulates the mitotic spindle assembly factor NuMA.
BRISC binds and deubiquitinates the spindle assembly factor NuMA
Gpuccio,
Nice, glad videos are of help 🙂
I’ve yet to get through the papers you and Dionisio have shared.
Like at your #14 post…
“So, this is another example of two complex symbolic codes (histone code and ubiquitin code) strongly interacting, in a highly dynamic and articulated pattern.”
So which code arrived 1st? Simultaneous Code building by random mutations and natural selection?
Doubtful.
Obviously Histone must be in place or can you imagine the journey along the length of DNA not packaged by Histones?
And did ubiquitin just pop up one day and say, voila, I’m code and recognize histone binding targets and building pathways for DNA repair?
Obviiously, I’m being a bit loose and humorous, but there’s a point. And simple questions.
If the two codes do not arise at same time or not built simultaneously working together, then what?
So neo-Darwinist have addressed this, but how adequate is their explanation?
What happens if ubiguitin code and enzyme regulation are not available?
What happens to DNA Repair?
And how often is repair required, double-stranded that is?
Curious what neo-Darwinist propose as evolutionary history for multiple codes, pathways, signal recognition and repair functions rising together. As well as coordination of these systems.
Will have more time to review tonight.
Very good work Gpuccio! Thanks again 🙂
Dionisio:
I have been missing your support! 🙂
Yes, mitosis and cell division seem to be under the realm of ubiquitin control, too.
About the paper you referenced at #22, it is rather surprising how some concept constantly recur in ubiquitin literature. For example, just from the abstract of this paper:
dynamicity
plasticity
versatile
fine-tune
variety
signals
conceptual challenges
Maybe my focus on semiosis in the OP is not so bad! 🙂
Dionisio:
Fig. 1 of the same paper is a very good summary of:
“Writing, reading, and editing ubiquitin.”
Semiosis everywhere!
Fig. 2 from the same paper is a very good summary of cullin based modular proteins, and it adds the even more complex APC/C structure (at least 14 different subunits!). From the Legend of the Figure:
DATCG:
Thank you again for you very good thoughts.
I would like to add some comments about the points you make, but I have not the time now. I will come back later! 🙂
DATCG:
Histone code, Ubiquitin code, cell signaling, and many other things, are essentially new layers of complexity that appear in eukaryotes, and become more stratified in metazoa.
My personal idea is that eukaryotes and metazoa require, just from the beginning, a whole new design approach that is based on many interacting levels of regulation networks.
And the key word is: semiosis and regulation.
Of course, high levels of semiosis and regulation are already present in prokaryotes. But the eukaryotic world seems to be structured according to new concepts, and here is where we start to see these many parallel levels of control, each of them extremely important for practically all cell functions, each of them relatively independent, and yet each of them intertwined with all the others.
So we have all the epigenetic layers of transcription regulation, which multiply the possibilities of a rather static genome: DNA methylation, histone code, chromatin remodeling, and so on.
And we have the infinitely intricate netwotk of TFs, with their combinatorial working.
And then the complex post-transcriptional regulation, the intron system, the spliceosome, miRNAs, lncRNAs.
And a lot of different PTMs, including the Ubiquitination System which is the object of this discussion.
And, last but not least, cell to cell signaling, and the multitude of signals and receptors and of transmission pathways that convey the symbolic meaning of the signal from the membrane receptor, through definite intemediate steps, and ultimately to the TF network and DNA.
The amazing thing is that there is not one of these levels which does not control the same things as all the other levels, but in different ways, and that is not strictly interconnected with all the other levels. It’s like a multiple control strategy whose complexity grows exponentially, and whose ultimate purpose can only be to attain functional outcomes which would be absolutely impossible without control, or with single level control.
You ask: “So which code arrived 1st?” I think that the obsvious answer is: they are all part of the same project, they were conceived and implemented in a parallel process, just from the beginning, to realize a design of increasing complexity and efficiency of which we no equivalent is known.
Dionisio:
The bacteroides paper you link is really intriguing. It seems an obvious case or HGT with adaptation, but it is certainly atypical and stimulating.
The most amazing fact is that this ubiquitin-like protein is used as a toxin against similar bacterial species. Infortunately, the mechanism of action of the protein in that role has not been clarified. that would really be interesting.
It’s interesting that the authors have no doubts that the bacterial protein was acquired, either from eukaryotes or from giant viruses. So, they opt for HGT just from the beginning.
That seems obvious to me too, with the protein having 67% identities and 84% positives with human ubiquitin (bitscore 108 bits, E value 2e-38). It is clearly a derivation from eukaryotic ubiquitin. But I think a pure neo-darwinist could also propose some form of convergent evolution, or what?
The simple truth is: 108 bits of information require an explanation. That’s why the authors state (rightly): “The source from which ubb was acquired is not clear from existing genomic sequences.”
OK, but what about the thousands of bits that appear in thousand of individual protein, for example, at the origin of vertebrates? Or in eukaryotes? Don’t they deserve some explanation too?
Am I asking too much? 🙂
Hello GP, I am just now seeing your fantastic OP.
Man’o man, GP, what a wonderful job you’ve done in explaining the system and highlighting the scope of the issue. If you don’t write a book, then there is something truly wrong with the world.
I’ve just read the OP, haven’t read the comments.
It all functions via semiosis — from the very start.
GP, you and I once spoken briefly about Marcello Barbieri holding his annual “Code Biology” conference in Italy. I suspect this is precisely the type of information covered in those labs and presentations.
GP, your presentation is just excellent. Where are your opponents, my friend? I don’t see them. Are there no faithful left to carry the RV+NS banner into battle?
Reading this:
….sounds real familiar. 🙂 🙂
It reminds me of this… (if I may):
Perhaps Art Hunt will stop by and pick up on this excellent OP (and also get back to the unfinished business from your previous OP as well).
🙂
Gpuccio…
Thanks for your follow-up and answers. Quickly #30.
I agree with it being a coordinated, parallel process. And I take note of your thoughts…
Agree with “require… whole new design approach”
And new codes. Codes that must be interpreted, recognized
and functional.
Hardly amenable to random mutations. The amount of just-so happenstance for multiple proteins, signals and systems to simultaneously coordinate seem to be insurmountable.
Good to see you UB. Was responding on GPuccio’s other point.
#30 in his line below…
Yes, and look forward to hearing from UB on semiosis.
———————-
🙂 ha! Great timing UB. I almost posted then saw your comments.
So funny as I found your post form March 2016 just minutes earlier and was reading it and about Marcello Barbieri.
Here is his autobiography…
Marchello Barbieri Autobiography
.
#37 UB
Arthur Hunt, one can hope.
I thought he might provide some good insight on evolution of the Spliceosome via some of the comments he put forward.
But nothing since then.
From Barbieri’s autobiography page, interesting to note…
How many other codes not included or to be found in future?
Layer upon layer.
I think Gpuccio is on target re: semiosis and regulation.
.
Yes, Barbieri is an interesting fellow, and I surely appreciate his work. But there is a real problem — setting aside for a moment the fact that he denies any room for design in biology. I can mentally work around that issue, but he also seams to find some difficulty is reconciling the encoding of biological information and the Peircean concept of interpretation. He sees them in some strange conflict with one another.
I truly don’t get his issue there. As far as I can see, Pattee put that issue completely to bed decades ago in the late 1960s. The actual physics of the system shot the deciding point. There is no such thing as a code without interpretation.
– – – – – – – –
anyway, not taking GP’s excellent OP off course
No question about it.
Pattee, 1969
How do we tell when there is communication in living systems? Most workers in the field probably do not worry too much about defining the idea of communication since so many concrete, experimental questions about developmental control do not depend on what communication means. But I am interested in the origin of life, and I am convinced that the problem of the origin of life cannot even be formulated without a better understanding of how molecules can function symbolically, that is, as records, codes, and signals. Or as I imply in my title, to understand origins, we need to know how a molecule becomes a message.
Upright BiPed (and DATCG):
Welcome! 🙂 🙂
It was really a beautiful surprise to awaken and find your many comments here!
And your beautiful discussions with DATCG too…
I was certain that you would like the semiosis angle. 🙂
OK, our interlocutors, as usual, are nowhere to be seen, but at least I have some true friends! So thanks be given to you, DATCG, Dionisio. 🙂
I am in a hurry now, so I will be back as soon as possible for some comments. I just wanted to thank all of you.
Upright Biped:
“sounds real familiar”.
And it is!
There are many similarities with the best known example of semiotic system in biology: the genetic code.
I would like to make a few reflections on the similarities and differences between the two systems:
Nature of the code:
The genetic code is in some measure more clear-cut. While redunndant, it is certainly strict and context independent. Codons have one unequivocal meaning.
The ubiquitin code, like many other biologcial codes, seems to be nore fluid, and probably more context-dependent. In a sense, these seem to be higher forms of code, serving a more complex function.
However, one specific feature of the ubiquitin code is that it relies practically on one single molecule, ubiquitin (and a few minor variants), and the main nature of the alphabet depends on the variety of chains that can be realized using the 8 internal switches. In that sense, there is an homogeneity of the tool which remind the genetic code, while other symbolic systems (like signal receptor systems) have greater variation and specificity in the nature of the signal.
Writing the code:
This is probably the gratest difference between the two systems. The information content coded by the genetic code is pre-existent. It is not written by the cell, it is simply inherited. In a sense, the information is written by the designer (ID point of view) or by the RV + NS process (neo-darwinist point of view). Indeed, one of the main objections against “third way speculations” is that there is no known mechanism in the cell that allows a flow of information from the phenotype to the genome (protein coding genes): IOWs, the cell does not know how to write new information (existing in the phenotype) at the level of protein coding genes.
On the other hand, the information coded by the ubiquitin code is written by the cell: it is essentially epigenetic information, not heritable genetic information. Of course, the writing is probably guided in some measure by the genome, and probably in some other measure by the epigenome, but the writing itself is implemented by the individual cell.
More in next post.
Upright Biped:
Let’s go on with the comparison between the Ubiquitin Code and the Genetic code.
Reading the code:
The genetic code, as we well know, is read by the 20 Aminoacyl tRNA synthetases, through the correctly charged tRNAs. This is where the code is really understood.
The Ubiquitin code is similarly read by a number of specific proteins (maybe 40 – 100) which share a number of ubiquitin-binding domains (UBDs): about 20.
So, the reading system seems to be a little more complex here, but essentially comparable to the reading system in the genetic code.
The final effector:
Here, too, the genetic code system seems to be relatively simpler: the final effector is the ribosome, and translation. However complex this is, it is still a rather homogeneous task.
Not so in the Ubiquitin System: while there is one major effector (proteasomal degradation), we have seen that it is not the only one: indeed, a lot of important effects, in almost all cell systems, are mediated by specific effects on different protein – protein interactions and protein configurations, without involving proteasomal degradation in any way.
More in next post.
Upright Biped (and DATCG):
And, finally:
The complexity:
While all the coding systems we have considered (and I would say all those quoted by DATCC at #41 from Barbieri’s autobiography page) are certainly hugely complex from any functional point of view, still the Ubiquitin System has a very special feature: the very high number of individual proteins involved.
Indeed, with about 1000 proteins involved specifically in the system, it is probably the cellular process with the greatest number of protein coding genes in the genome. We must remember that 1000 protein coding genes out of 20000 is almost 5% of the whole protein coding genome.
The only other example which comes to mind is olfactory receptors, which corrspond to about 1000 in the mammalian genome (but only 400 active in the human genome).
But olfactory receptors are a class of not too long proteins which share a great sequence homology in many cases (50% or more), and so appear to be a diversification of similar molecules.
Instead, E3 ligases, which make up the greatest part of proteins involved in the Ubiquitin System (600+), are a set of really distinct proteins, except for the shared domians. But, as already said, the shared domains are in general a minor part of the molecule. The RING domain, for example, which characterizes most of E3 ligases, is only 40 – 60 AAs long: in a class of proteins which has a mean length of about 500 AAs, that is certainly a minor part of the sequence information.
The rest of the sequence is certainly involved in the specific function of each E3 ligase: to recognize the correct target protein, in the correct context. And each of the 600+ E3 ligases is completely different from each other in that respect.
That makes a real lot of specific functional information in the system.
Even from a proteomic point of view, the system represents a huge part of cell resources, its proteins amounting to about 1.3% of the total cell proteins, as stated here:
The demographics of the ubiquitin system.
http://www.cell.com/trends/cel.....15)00054-9
Many cell resources are used in many systems to generate variety. But while in some systems, like the immune system, variety is created using controlled variation on a limited number of genes, in the ubiquitin system (like in the olfactory system) variety is mostly paid for at genomic level. So, a lot of resources in the genome and the proteome are committed to that, an most of the sequence functional information is directly coded in the genome.
Just adding to our list of cell processes finely regulated by the Ubiquitin System. What are we missing?
The central nervous system? Neurons? Synapses?
Neuronal ubiquitin homeostasis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758786/
Nedd4 and Nedd4-2: ubiquitin ligases at work in the neuron.
Seven in Absentia E3 Ubiquitin Ligases: Central Regulators of Neural Cell Fate and Neuronal Polarity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646344/
Spatial Organization of Ubiquitin Ligase Pathways Orchestrates Neuronal Connectivity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622823/
See in particular Fig. 2 and Fig. 3.
And so on, and so on…
Fascinating isn’t it. The cell is telling you what it is; layers of interdependence, and always yet another layer to be understood.
I am interested in how that compares numerically to the prokaryotic system.
#48. I really appreciate the numbers you’ve thought through and placed in your presentation. Understanding context is a real bonus for your readers.
#42-44 UB,
yes, I can work around it too. I found it a bit amusing to a degree. What he’s advocating is screaming Design.
The Codes, The Codes! 😉
It’s why I posted them.
I’ve not time to read Pattee, which I briefly looked at on your earlier post. Will look again when time permits.
Pattee is right, your quote sums it up nicely.
Indeed how is a correct code understood to be correct?
After a billion, maybe trillion combinations?
Hmmmmm. Where and when does time and resources become a factor?
As more function in “junk” DNA is found, the limits to such random “success” becomes smaller as well.
Will Dan Graur’s threshold for “junk” DNA hold? Will he be found correct, or ENCODE correct and as Dan said, “evolution is wrong?”
.
Sorry for this off topic question:
Can this be considered a code issue too?
Decoding temporal interpretation of the morphogen bicoid in the early drosophila embryo
Huang, A & Amourda, C & Zhang, S & Tolwinski, Nicholas & Saunders, Timothy. (2017). eLife. 6. . 10.7554/eLife.26258.
Morphogen gradients provide essential spatial information during development.
Not only the local concentration but also duration of morphogen exposure is critical for correct cell fate decisions.
Yet, how and when cells temporally integrate signals from a morphogen remains unclear.
Here, we use optogenetic manipulation to switch off Bicoid-dependent transcription in the early Drosophila embryo with high temporal resolution, allowing time-specific and reversible manipulation of morphogen signalling.
We find that Bicoid transcriptional activity is dispensable for embryonic viability in the first hour after fertilization, but persistently required throughout the rest of the blastoderm stage. Short interruptions of Bicoid activity alter the most anterior cell fate decisions, while prolonged inactivation expands patterning defects from anterior to posterior. Such anterior susceptibility correlates with high reliance of anterior gap gene expression on Bicoid. Therefore, cell fates exposed to higher Bicoid concentration require input for longer duration, demonstrating a previously unknown aspect of Bicoid decoding.
DATCG,
Barbieri wrote an paper, I think entitled “A Short History of Semiotics”, where he recounts the point in time when all the various factions of semiotic thought came together and sought to work together. He describes two postulates that help forge the agreement to come together. The first postulate (recalling from memory) is that semiosis and life are coextensive, i.e. one does not exist without the other. And if you read the paper, he goes on to fully support that postulate. The second postulate, however, was that they (the group) would have nothing to do with any argument for design in biology. Never again throughout the paper is the design argument even mentioned, other than to kill it up front.
The fact that this kind of maneuver was seen as necessary says quite a bit about the argument for design.
Gpuccio,
On your original post you mention Ubiquitin Code and UPS in relation to Autophagy above.
The paper in that section is behind a paywall. I found some interesting info to add, an Open Access Book –
Chapter 7 The Role of Ubiquitin System in Autophagy
from 2016.
Book Link Here-Chapter 7 Role of Ubiquitin in Autophagy
Specifically on role of Ubiquitin and DUBS, modifications and Selective role in cargo packages for degradation. Pointing out autophagy “was originally thought to be non-selective” via random process for degradation.
But as is highlighted here and through chapter 7, Ubiquitin and DUBS play a role in tagging cargo for recognition and selection, not random but induced by stress for example.
This is something I’d expect from an epigenetic point of view. The higher level code using signal processing, tagging as intervention whether positive or negative.
Not to get off any central points. But guide us where you would like to focus 🙂
And in conclusion from Chapter 6….
#55 UB,
Thanks, I caught a bit of that in his autobiography, not to such detail.
Yes, agree. It’s a narrative they must stick to while oppressing any thought other than a materialistic, blind point of view of a “blind” “unguided” process.
It’s an overall area to address by you and Gpuccio’s other comments he extended really well on Reading, Writing Code and comparisons of Code, a Base, Copying and Higher levels of Code.
Ubiquitin turnover and endocytic trafficking in yeast are regulated by Ser57 phosphorylation of ubiquitin
re: #57 in reference to you UB and Gpuccio.
I was trying to Edit, but to late.
I thought the area covered by Gpuccio, semiosis and your comments on Barbieri, Codes, etc., symbols and recognition by Pattee, overall selective processes would be interesting to expand upon as well in more detail.
GP, if I understand correctly, exactly how the medium is read is still being discovered. Perhaps I am wrong about that. I’ll have to find the time to study it. But from my own perspective, I would be interested in exactly what distinguishes one referent from another, and exactly how the system (process) acquires that from the medium.
The Quipus
For me, it matters how I would categorize the system in comparison to other systems.
— again, great OP and further comments.
#54 Dionisio,
How’s this?
Check out the following PDF paper…
The emergent design of the neural tube: prepattern, SHH morphogen and GLI code
Notice where it’s published 😉
Hint: Barbieri
UB, think you might enjoy the following from the main page at the link I provided Dionisio. You may already read it…
.
DATCG,
Here are some Pattee papers (among others) you might find interesting at some point.
Bibliography
The thing I appreciate about Pattee is that he is careful in his thoughts. He doesn’t force conclusions into his descriptions.
Just imagine the rarity of that particular trait among researchers into the origin of life. There is even a point in one paper where Pattee (after giving a fairly comprehensive description of the issues) simply and briefly says that perhaps there was a time in distant history (paraphrasing) that chemistry acted differently than has at any time since. The man wasn’t trying to be clever; I believe it was a genuine puzzlement from a scientist who isn’t going to give up on (skew) a honest scientific analysis because of his own metaphysics.
That trait (and the fact that he wrote about these issues for 50 years) is obviously endearing. He retired from writing a couple of summers ago. I’d say the scientific enterprise got their money’s worth.
So much more to cover, not enough time. But Code Biology is Design Biology.
And I thought what Gpuccio summed up here…
is important.
will check in later 🙂
Upright Biped, DATCG, Dionisio (and, of course, butifnot):
It seems that we are having quite a private party here.
A little bit staggered, I suppose, because of time zones and probably of my sleeping habits! 🙂
However, it’s great to find your precious comment in the morning, and to answer them later. After all, do we really need the interventions of our courteous (but a little shy) interlocutors from the other side?
No problems, the discussion is great, and we are deepening many interesting issues.
As the song says:
“Oh I get by with a little help from my friends” 🙂
Upright Biped:
“I am interested in how that compares numerically to the prokaryotic system.”
Do you mean to whole prokaryotic genomes?
Well, E. coli, which is a medium sized bacterium, has about 4000 protein coding genes. Some bacteria have less than 1000 protein coding genes.
If you mean how the eukaryotic system compares to its supposed ancestors in prokaryotes, you can look at this paper:
Prokaryotic Ubiquitin-Like Protein Modification
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757901/
It seems that the prokaryotic analogs of ubiquitination, although certainly interesting, are rather different under many aspects, and much simpler.
For example, the two main prokaryotic ubiquitin-like proteins, Pup and UBact, show no significant sequence homology with the ubiquitin sequence.
The proteosome exists in prokaryoyes (some bacteria, all archaea), but it is much simpler, too. See also here:
PROKARYOTIC UBIQUITIN-LIKE PROTEIN, PROTEASOMES, AND PATHOGENESIS
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662484/
“In contrast to eukaryotic proteasomes, core particles from archaea and bacteria are far simpler structures with homo-heptameric rings of catalytic ? subunits flanked by homo-heptameric rings of ? subunits16–21 (Table 1, Fig. 2). To date, only bacteria found in the class Actinomycetes are known to have proteasomes19, 22–24. Multi-subunit regulatory complexes similar to those in eukaryotes have not been identified in prokaryotes, suggesting the mechanisms by which proteins are targeted for degradation are different, or that regulatory complex interactions with cores are transient or weak.”
DATCG:
“Indeed how is a correct code understood to be correct?
After a billion, maybe trillion combinations?”
That’s exactly the point. Codes cannot really emerge without design, because they essence is a symbolic relationship. There is absolute no way of getting them in other ways. There must be an understanding of meaning, just from the beginning.
Codes are structures where something means something else, by arbitrary choices. They scream design and conscious understanding, even in the simplest forms.
That’s why noe-darwinists have tried in all possible ways to derive the genetic code from ancient biochemical affinities, of course without succeeding. Their only hope is to demonstrate that the origin of the code is not symbolic, and that the mapping is not arbitrary.
But that is simply not true, and they will never succeed.
Dionisio:
“Can this be considered a code issue too?”
This is a difficult question. In brief, what I think is as follows:
The bicoid gradient is certainly a signal, a signla that could bo cosncidered as a wave of concetrations in space (cell locations) and time (time windows).
My only problem in considering it a coded signal is that bicoid apparently acts as a transcription factor, directly activationg other genes to get the desired results.
I am more at ease with the concept of symbolic coding when the system includes some independent actor which reads and inteprets the signal, like ubiquitin-binding proteins, for example. TFs are more similar to final effectors.
So, I would say that it is certainly a signal, but I would be cautious in stating that it is a coded signal.
Two words: “information jump”
🙂 🙂
Upright BiPed:
Our personalities are strangely merging one with the other! 🙂
Upright Biped:
“The second postulate, however, was that they (the group) would have nothing to do with any argument for design in biology. Never again throughout the paper is the design argument even mentioned, other than to kill it up front.”
This is very sad.
DATC at #56:
Wonderful contribution.
Autophagy by lysosomes is an important alternative degradation pathway, with different specificities compared to the proteasome pathway. It is mentioned in the table in the OP, as connected usually to K63 ubiquitinations, but it is absolutely appropriate that you have given more detail about this other fascinating outcome.
I agree with you that, even if the Ubiquitin System seems to regulate, start and terminate the whole process (as detailed in Fig. 1), the most interesting part seems to be the role in selective autophagy, where the cargo is recognized and transported in a very specific way (as detailed in Fig. 2).
A specially interesting issue is certainly mitophagy, the degradation of mitochondria.
A central role in that process seems to be implemented by Parkin, an elusive E3 ligase whose mutations are known to cause a familial form of Parkinson’s disease known as autosomal recessive juvenile Parkinson’s disease (AR-JP).
Parkin is a member of the RING-between-RING (RBR) family of E3 ligases, the least common class of these proteins. It has quite a lot of functions listed on its Uniprot page, from which I quote this very interesting statement:
Emphasis mine.
It seems that context dependency is the rule, here. These processes are wonderful examples of Context-oriented Programming and Object-oriented Programming of the best kind! 🙂
gpuccio @69:
I see your point, which makes sense. Thanks.
The final effect of the morphogen gradients, which are spatiotemporal signaling profiles, depends on many factors, like the location of the sources, the type of signaling molecules, the source activation/deactivation timing, the secretion rate, the transporting of the signaling molecules to their destination, their concentration distribution, the duration of the exposure of the target cells to the spatial concentrations of signaling molecules. But none of that seems associated with codes.
Interestingly the control of such a fascinating component of morphogenesis is done directly though signals.
DATCG, UB, gpuccio,
Biosemiotics doesn’t seem to apply directly to spatiotemporal signaling profiles (a.k.a. morphogen gradients), which are important choreographic components of developmental biology and evo-devo.
Is this correct?
hanks.
@75 correction
Thanks
Dio,
I can’t answer your question just now. Using the word “signal” does indeed seem to indicate semiosis — I.e. a signal is a semiotic element within a system. But I would have to study the system in detail in order to answer the question with any sense of certainty on my part. But I have my hands full right now, and just cannot do that at this time. GP likely already knows the system and can tell you.
….my apologies
Upright BiPed:
Thank you for the Quipus! 🙂
You are right, the way the ubiquitin signal is read in different cases is often only partially understood.
For example, even in the case of the proteasome, which is certainly the most studied scenario, many things are stil elusive.
See for example this very recent paper:
Recognition of Client Proteins by the Proteasome.
https://www.annualreviews.org/doi/full/10.1146/annurev-biophys-070816-033719#f1
(Paywall)
Or this other one:
Ubiquitin recognition by the proteasome.
J Biochem. 2017 Feb 1;161(2):113-124. doi: 10.1093/jb/mvw091.
Much is still to be understood.
UB @77,
gpuccio covered that @69. However, let’s leave this off topic issue which I mentioned for curiosity but it’s a distracting digression from the main discussion in this thread.
Thanks.
Is this just my perception?
After this OP + follow up discussion, now the term “ubiquitin” seems to pop up in many places out there.
Perhaps this thread has increased our sensitivity to detect that term?
Or is it that the term is really appearing more often lately?
Maybe both?
Blame it on gpuccio!
🙂
Background
Parkin (PARK2) is an E3 ubiquitin ligase that is commonly mutated in Familial Parkinson’s Disease (PD). In cell culture models, Parkin is recruited to acutely depolarised mitochondria by PINK1. PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy. Many substrates have been identified using cell culture models in combination with depolarising drugs or proteasome inhibitors, but not in more physiological settings.
Methods
Here we utilized the recently introduced BioUb strategy to isolate ubiquitinated proteins in flies. Following Parkin Wild-Type (WT) and Parkin Ligase dead (LD) expression we analysed by mass spectrometry and stringent bioinformatics analysis those proteins differentially ubiquitinated to provide the first survey of steady state Parkin substrates using an in vivo model. We further used an in vivo ubiquitination assay to validate one of those substrates in SH-SY5Y cells.
Results
We identified 35 proteins that are more prominently ubiquitinated following Parkin over-expression. These include several mitochondrial proteins and a number of endosomal trafficking regulators such as v-ATPase sub-units, Syx5/STX5, ALiX/PDCD6IP and Vps4. We also identified the retromer component, Vps35, another PD-associated gene that has recently been shown to interact genetically with parkin. Importantly, we validated Parkin-dependent ubiquitination of VPS35 in human neuroblastoma cells.
Conclusions
Collectively our results provide new leads to the possible physiological functions of Parkin activity that are not overtly biased by acute mitochondrial depolarisation.
Martinez Zarate, Aitor & Lectez, Benoit & Ramirez, Juanma & Popp, Oliver & D Sutherland, James & Urbé, Sylvie & Dittmar, Gunnar & J Clague, Michael & Mayor, Ugo. (2017). Quantitative proteomic analysis of Parkin substrates in Drosophila neurons. Molecular Neurodegeneration. 12. . 10.1186/s13024-017-0170-3.
Dionisio:
Seems quite a lot of work for one protein!
Thank you for the quote. 🙂
DATCG:
Interesting paper. And the world “design” in the title is precious: is the neo-darwinist surveillance becoming more distracted? 🙂
These three GLI proteins are interesting. They appear in vertebrates (while SHH is older). An interesting pattern of morphogens – TFs interacting.
Checking in for updates and reading before heading out 🙂
Thanks for all the expanded info Gpuccio. UB and Dio as well. Not sure when I’ll have time to review Pattee, but looking forward to it.
#5 Gpuccio,
Yes it raised eyebrows for me when I first read it. And the video clarified some more.
A review of “unstable” in terms of thermodynamic stability and protein folding? Or reversible? For steady-state levels to be efficient and fast. Maybe if you have time.
Question, is there a standard steady-state efficiency rate to maintain and how efficient must it be? If it’s even considered to be something important to track.
We tend to see high efficiency in many functions, like ATP or photosynthesis, but a balancing act is a bit different so would we expect more flexibility too in this area? Or, am I covering the same area you already mentioned Gpuccio?
If the balance between synthesis and degradation is not maintained, then accumulation of unstable proteins increase.
I’m curious what happens at different levels of low and high production synthesis vs degradation and at what point does the balance tip over.
Which suggest a next question, is there a master monitor reporting and/or more regulators of this balancing act.
I’m getting off subject, but it reminds me of the intricacy of each element, “cargo,” tagging, signals and systems coordinating together.
again from your original #5 post Gpuccio…
YES, So this “flexibility” must be “maintained” as such. Yet another area important for Monitoring, Alerts-Signals, Repair and critical function.
So somehow “junk” dna and or genetic mutations are supposed to mutate stable and unstable proteins? Step by step that is for interaction among all these systems.
Really like how you summed it up in last sentence.
Makes me think I need to replenish with healthy foods to maintain good balance, yet far from equilibrium 😉
I came across open access Book CMMP – Condensed Matter and Materials Physics, a Chapter with interesting history and how physics has a role in Biology, a bit dated from 2007…
What is the Physics of Life?>
quote…
“One of the entral problems faced by any organism is to transmit information reliably at the molecular level. This problem was phrased beautifully by Schrodinger in “What is Life?,” a series of lectures given(1943) in the wake of the discovery of () genetic information.”
() edited
Not recommending reading chapter. But there’s more on error processing I found in agreement.
Life requires all the sciences and a multi-disciplinary approach to understand it far from-equilibrium.
Also found this in Far From-Equilibrium Chapter…
The Next Decade
“… far from-equilibrium behavior is not rare but ‘ubiquitous’, occuring from the nanometer scale on up…”
Could not resist 😉
Haha, have a good day guys!
.
#83 Gpuccio,
Haha, I thought so re: Design. But was interesting finding
another code too. And noticed the Code Biology page includes it, along with another code discovered in 2014-2015.
I’ve not looked at morphogens at all. Another day 🙂
Dionisio at #80:
So, ubiquitin is becoming ubiquitous. There is some logic in that.
RV + NS can certainly explain that all! 🙂
Dionisio, DATCG, Upright Biped:
What about immunity, both innate and adaptive? What about T and B cells?
Innate immunity:
Multifaceted roles of TRIM38 in innate immune and inflammatory responses
https://www.nature.com/articles/cmi201666
(Paywall)
TRIM38 is a RING E3 ligase, whose sequence is specially engineered in mammals.
See also here:
TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis.
In plants?
Conventional and unconventional ubiquitination in plant immunity.
More in next post.
Dionisio, DATCG, Upright Biped:
Adaptive immunity?
Regulation of T helper cell differentiation by E3 ubiquitin ligases and deubiquitinating enzymes.
(Paywall)
See also here:
The ubiquitin system in immune regulation.
And this is a very good and very recent review:
Ubiquitin enzymes in the regulation of immune responses
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490640/
(Public access)
Abstract
Ubiquitination plays a central role in the regulation of various biological functions including immune responses. Ubiquitination is induced by a cascade of enzymatic reactions by E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase, and reversed by deubiquitinases. Depending on the enzymes, specific linkage types of ubiquitin chains are generated or hydrolyzed. Because different linkage types of ubiquitin chains control the fate of the substrate, understanding the regulatory mechanisms of ubiquitin enzymes is central. In this review, we highlight the most recent knowledge of ubiquitination in the immune signaling cascades including the T cell and B cell signaling cascades as well as the TNF signaling cascade regulated by various ubiquitin enzymes. Furthermore, we highlight the TRIM ubiquitin ligase family as one of the examples of critical E3 ubiquitin ligases in the regulation of immune responses.
Always for lovers of simplicity, I recommend Fig. 3, which covers Ubiquitin enzymes in the T Cell Receptor signaling pathway.
The B cell pathway is also covered in Fig. 5.
Fig. 6 is, again, about the NK-kB pathway, which is central in many immunity related processes.
And Fig. 7 is about our old friend, TRIM.
Dionisio, DATCG, Upright Biped:
So, here is a brief list of the cellular processes we have touched in the OP and discussion:
a) Proteasome degradation
b) Autophagic degradation
c) Mitophagy
d) Cell signaling and transmission pathways
e) Double-Strand Breaks DNA repair
f) Neuronal regulation
g) Regulation of innate immunity
h) Regulation of adaptive immunity
i) Regulation of T cell and B cell differentiation
It’s a lot of stuff, I would say.
And in each of those processes ubquitination has a major role.
And in each of those processes different proteins, especially different 3 ligases, are involved, often many different ones at a time, each of them complex, each of them usually involved in multiple scenarios.
Fascinating.
Dionisio, DATCG, Upright Biped:
Ah, I was forgetting. Our party is still very private.
And contributions from the other side? OK, let’s me count them…
Zero?
Dionisio, DATCG, Upright Biped::
Just a curiosity. Look at this 2016 paper:
Identification of Top-ranked Proteins within a Directional Protein Interaction Network using the PageRank Algorithm: Applications in Humans and Plants
http://www.caister.com/cimb/v/v20/13.pdf
(Public access)
I quote:
So, No 1 human protein (according to this classification, of course) is a RING E3 ubiquitin ligase.
And look at the 8 proteins which are included in the top 50 in all three ranking approaches. Some are membrane receptors, or kinases. But two of them, TRAF2 and TRAF6 (TNF receptor-associated factors) are RING E3 ubiquitin ligases, too.
In particular, they are both old friends: see the NF-kB section in the OP.
#80 Gpuccio,
I’m beginning to think these post deserve UD reserve space precisely because of the loaded content in your original post and how you lay it out for readers to observe and contemplate in the comments.
That list is a a great example you put together. All can be expanded into deeper branches and sub-list.
You included Neuronal Regulation above and a paper earlier. I briefly searched ubiquitin along with FAS – Fetal Alcohol Syndrome and Ethanol.
After the tragedy involving Parkland, Florida students at Marjory Stoneman Douglas High School in Broward County and the shooter Nikolas Cruz, neural disorders were of interest.
Some news reports speculated Cruz suffered from FAS. I don’t know if it’s been confirmed.
I came across an interesting paper, but waited to post since there’s so much to read.
Note: TLR4, ubiquitin-proteasome-pathway, autophagy-lysosome-pathway,
Here’s link and a few quotes Gpuccio as it ties in with your points on 1st Video by Deshaies, starting at 2:39 mark.
takeaway from above quote:
Delicate Balance, epigenetics, mutations harm, not enhance, resulting in “abnormal accumulation and aggregation of specific proteins.”
Effects mediated by TLR4 knockout. But look at the accumulation again and delicate balance.
off-balance
Paper Link, Open Access 2014…
TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain
.
GP,
I am going to have limited access for a few days, but there’s nothing substantial I can add to your excellent explanation of the Ubiquitin system. I rank this thread as one of the best to appear on UD in recent memory, and I haven’t even the slightest question as to why your opponents are absent from the conversation. Congratulations.
Reading this OP and your comments, I think about all the layers of control. Control systems have a necessary dual role to play; where they first make variables physically possible, and then they specify variables among the alternatives. And of course, all of this is established by a simultaneous coordination among the constraints that bring the system into being. One doesn’t exist without the other. The constraints can’t persist without the coordination.
I also think about your discussions on “information jumps”, and of how those jumps (from their very start) have had discoverable physical consequences. I’d like to pass on an extended quote (sorry about the length). This is 45 years old, and on substance, it stands up today and will be standing up tomorrow as well:
DATCG at #85:
Protein stability and protein half-life seem to be a very complex issue.
Portein half life in human cells seems to vary a lot. Here is a global proteome analysis:
A Quantitative Spatial Proteomics Analysis of Proteome Turnover in Human Cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316722/
Fig. 3 sums up some important results. In the 10% proteins with fastest turnover, half-life seems to vary from almost 0 to about 8 hours. A gross distribution of protein classes in the two extreme groups (slowest and fastest 10%) shows interesting differences. I quote from the paper:
This study was performed on HeLa cells, so things could be different in normal cells in vivo.
An interesting paper is the following:
Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution
https://www.sciencedirect.com/science/article/pii/S2211124714006391
This is very interesting, because if we (reasonably) assume that a shorter half-life is often related to critical regulatory functions, then it seems that intrinsically disordered segments, in particular at the N-terminus, could be also related to regulatory function.
Which is an idea that I would very happily endorse! 🙂
UB @94,
Interesting assessment of GP’s latest OP and follow-up comments.
Thanks.
DATCG @93:
That’s an interesting paper related to the effects of human behavior on the complex ubiquitin proteasome that GP has presented to us here.
Thanks.
DATCG @93:
Another potential association of the ubiquitin proteasome with serious health-related issues:
DATCG @93:
Another potential association of the ubiquitin proteasome with serious health-related issues:
[emphasis added]
gpuccio @95:
Who wouldn’t?
🙂
#94 UB,
Here Hear, Gpuccio’s done another great post.
Thanks for your comments and additional sources as well on
Pattee. I’ve enjoyed reading the snippets and quotes you’ve
posted. And look more to reading about and from him in
future.
Dionisio,
thanks, the amount of health issues is as
endless as ubiquitin appears to be in it’s arrangements
and coordinations.
I’ve saved ncbi searches on this for now to go back and
review.
#95 Gpuccio, thank you, will follow up on reading these
as well!
Please do not make another major post for another few weeks
😉 haha, as I need time to consume this vast information
ubiquitin proteosome system, DUBs and more intricate
details.
DATCG,
Let me repeat the comment that was posted 5 days ago @21:
“This thread has too much bad news for the ‘modern synthesis’ and the ‘third way’ clubs.”
DATCG @103,
I can chew the information poured into this thread, but can’t digest it completely, not even close. There’s much more than I can handle, considering that practically everyday new data are thrown in the bucket. This is insane. And we ain’t see nothin’ yet. The most fascinating discoveries are still ahead.
gpuccio @95:
Apparently you’re right on this:
gpuccio @95:
Apparently you’re right on this:
gpuccio @95:
Apparently you’re right on this:
gpuccio @95:
Apparently you’re right on this:
Maybe a topic for a future OP?
Gpuccio, re: IDPs IDS’s, IDRs…
After reviwing your post and comments, I found a video on “Intrinsically Disordered Proteins and “unstructural biology” aquiring momentum over last decade. In it, the presenter shows “protein structure-function paradigm” over last 65 years has solved over 100,000 structures.
That’s great progress!
But, enter IDPs, gaining momentum. I refer back to your comments in #10…
“The theme of intrinsically disordered regions in proteins is becoming ever more relevant.”
and at #95
Thanks for your patience Gpuccio as I catch up and work through this.
If I’m not on right track, let me know. Glad for insight or corrections.
Old Paradigm – What was and still is:
Protein Seq A -> Function A
Protein Seq B -> Function B
Protein Seq C -> Function C …
vs new research emphasis on Dynamic Model:
This may be do to requirements for analog response? Not just digital. Like Heat Shock(or threshold stress levels)? That Dionioso quoted from another paper.
From a Design perspective – flexibility in a controlled format.
As feedback Dials up, Dials down, or rapid-response, quick thresholds, etc., signals and changing informational content carried from input processes of
internal or external demands to a real-time decision tree process.
Otherwise, as the presenter raised, how could it be handled?
How many rigid objects would escalate in number?
Because system demands for rapid interactions require response to survive
or not be negativealy impacted.
W/o Dynamic Objects how large or how inefficient is cost of maintenance?
Just basic production and navigation alone?
Strict rules importantly require strict enforcement. If Object is not
well defined the “compiler” or translation, transcription will not accept it
for specific uses.
I brought up a Rules Based logic some time ago utilizing Conditional
Processing. Can’t remember how far back, but as a programmer, I recognized
it immediately. Rules based works wonderfully with Variable Information
Reformatting btw, allowing flexibility like IDP’s, etc., including
reading in of real-time changes dependent upon known or unknown input
variables.
There is a purpose for strict, one-way ticket rule that must be
invoked, or rejected if not right.
But, how many Protein Sequences for Life if only route is a strict
Protein Sequence -> Function? W/o Dynamic Objects?
As an observation, only recently in 2010 did Microsoft introduce Dynamic
Object function in C# as a comparitive analogy. Not sure it’s a perfect
analogy in all substantiative cases.
But, by Design after all these years Microsoft added greater flexibility for coders at Run-Time. Enabling less code for more dynamic responses.
More efficient for Coders.
Note: Not verified efficiency of memory and processing run times. Obviously
there are trade-offs on management of size, efficiency, response time.
Design must take these into consideration. Materialist evolution only
cannot. It creates vast amounts of “junk” DNA, right?
I want to also recognize Dionisio’s efforts in past to highlight
Object-Oriented Code reference frame.
As you, UB and Dionioso have emphasized; semiosis, symbols and Code allow such verstailtiy.
This allows independent response w/o need for building another protein
sequence. Keeping proteins at resonable number.
Hmmmm… I’m tempted to use a well known innovators in shipping and receiving, not just FedEx but in product distribution. Amazon.
Input -> Dynamic Object -> Signal Out -> A million possible outcomes with final location and method for specific time-dependent delivery.
Which brings us back to Gpuccio’s discussion and UB’s highlighting of
“Information Jump”
Under archaea and bacteria IDPs and IDRs are below 5%
In Eukaryotes – IDP jumps to 20%, 30% for IDR
In humans – IDR jumps to 35%
.
Dionioso @105, no kidding, I need a NCBI wireless jack installed 😉
It’s a bit like The Matrix as Neo sees all the Data explosion of information but has not quite grasped how to use it. Before he mind bends the matrix, lol.
Upload Ubiquitin Code – Flash! Upload IDP,IDR,IDS! Flash!
DATCG,
as result of reductionist reverse-engineering approach to research, what we’re seeing in the scientific literature is like the cacophony produced by the orchestra musicians tuning their individual instruments separately… the actual symphony hasn’t started yet… the biological ballet choreography, with all its colorful splendor, hasn’t been presented yet… it’s all ahead. Just get ready to see more fascinating things in the future. Biology-related research is moving at a very accelerated pace.
The innate antiviral response is integral in protecting the host against virus infection. Many proteins regulate these signaling pathways including ubiquitin enzymes. The ubiquitin-activating (E1), -conjugating (E2), and -ligating (E3) enzymes work together to link ubiquitin, a small protein, onto other ubiquitin molecules or target proteins to mediate various effector functions. The tripartite motif (TRIM) protein family is a group of E3 ligases implicated in the regulation of a variety of cellular functions including cell cycle progression, autophagy, and innate immunity. Many antiviral signaling pathways, including type-I interferon and NF-?B, are TRIM-regulated, thus influencing the course of infection. Additionally, several TRIMs directly restrict viral replication either through proteasome-mediated degradation of viral proteins or by interfering with different steps of the viral replication cycle. In addition, new studies suggest that TRIMs can exert their effector functions via the synthesis of unconventional polyubiquitin chains, including unanchored (non-covalently attached) polyubiquitin chains. TRIM-conferred viral inhibition has selected for viruses that encode direct and indirect TRIM antagonists. Furthermore, new evidence suggests that the same antagonists encoded by viruses may hijack TRIM proteins to directly promote virus replication. Here, we describe numerous virus-TRIM interactions and novel roles of TRIMs during virus infections.
Tol, Sarah & Hage, Adam & Isabel Giraldo, Maria & Bharaj, Preeti & Rajsbaum, Ricardo. (2017). The TRIMendous role of TRIMs in virus-host interactions. Vaccines. 5. 23. 10.3390/vaccines5030023.
Sparrer, Konstantin & Gack, Michaela. (2018). TRIM proteins: New players in virus-induced autophagy. PLOS Pathogens. 14. e1006787. 10.1371/journal.ppat.1006787.
http://journals.plos.org/plosp.....=printable
The ubiquitin-proteasome system (UPS) ensures regulation of the protein pool in the cell by ubiquitination of proteins followed by their degradation by the proteasome. It plays a central role in the cell under normal physiological conditions as well as during viral infections. On the one hand, the UPS can be used by the cell to degrade viral proteins, thereby restricting the viral infection. On the other hand, it can also be subverted by the virus to its own advantage, notably to induce degradation of cellular restriction factors. This makes the UPS a central player in viral restriction and counter-restriction. In this respect, the human immunodeficiency viruses (HIV-1 and 2) represent excellent examples. Indeed, many steps of the HIV life cycle are restricted by cellular proteins, some of which are themselves components of the UPS. However, HIV itself hijacks the UPS to mediate defense against several cellular restriction factors. For example, the HIV auxiliary proteins Vif, Vpx and Vpu counteract specific restriction factors by the recruitment of cellular UPS components. In this review, we describe the interplay between HIV and the UPS to illustrate its role in the restriction of viral infections and its hijacking by viral proteins for counter-restriction.
Seissler, Tanja & Marquet, Roland & Paillart, Jean-Christophe. (2017). Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins. Viruses. 9. 10.3390/v9110322.
.
grrr, having network issues. Where’s ubiguitin flexibility and IDP when you need it! 😉
Dionisio,
Yes, agree. I came across another video, actually a
commercial for products, but found it interesting highlight
of the direction we’re heading.
I think often times real life business undercuts ideological differences by neo-Darwinist…
https://www.youtube.com/watch?v=ICz49GY24mI
can skip to minute 1:14
Look how fast the field and publishing is growing since first discovery up to 2014, time of video.
Also, nitpicking, but I hate the naming conventions,
Disorder?
There’s no disorder here and it’s confusing nomenclature in my opinion.
Flexible, Differential sure, but not disorder. It’s almost like calling unknown gemonic data – “junk” which is no longer junk.
Should be renamed I think. I get that they were naming it as an opposite function to “ordered” or Fixed 3D structures.
But really? Disordered? Why not call them IFPs?
Intrinsic Flexible Proteins, or Conditional Proteins, or Relaxed Proteins.
No, instead, unsuspected flexible, conditional order is called disorder.
Sigh. The naming conventions in biology, genetics, etc., have long suffered. It’s bothered me since my first biology class and only seems to be more mired today in same illogical naming conventions.
LOL, maybe too nitpicky, but I think half the problem with it is making logical naming conventions, also open it up to more understanding and people in general.
.
Gpuccio #95, thank you for this…
Distribution of protein turnover
“Fig 3 Proteins were sorted on the x axis from fastest to slowest turnover and represented as a scatter plot with the 50% protein turnover value on the y axis. Approximately 60% (blue lines) of the HeLa proteins show a 50% turnover”
.
Most TRIM proteins contain E3 ubiquitin ligase activity, a class of enzymes which catalyze the final step (E3 step) in the ubiquitination cascade to form an ubiquitin covalent bond with a substrate lysine.
[…] how zinc impacts MG53 E3-ubiquitin ligase activity and the identities of the E3-ligase substrates involved in MG53-mediated wound healing remain elusive and requires further investigation.
Wound care is a major healthcare expenditure. Treatment of burns, surgical and trauma wounds, diabetic lower limb ulcers and skin wounds is a major medical challenge with current therapies largely focused on supportive care measures. Successful wound repair requires a series of tightly coordinated steps including coagulation, inflammation, angiogenesis, new tissue formation and extracellular matrix remodelling. Zinc is an essential trace element (micronutrient) which plays important roles in human physiology. Zinc is a cofactor for many metalloenzymes required for cell membrane repair, cell proliferation, growth and immune system function. The pathological effects of zinc deficiency include the occurrence of skin lesions, growth retardation, impaired immune function and compromised would healing. Here, we discuss investigations on the cellular and molecular mechanisms of zinc in modulating the wound healing process. Knowledge gained from this body of research will help to translate these findings into future clinical management of wound healing.
Lin, Peihui & Sermersheim, Matthew & Li, Haichang & Lee, Peter & Steinberg, Steven & Ma, Jianjie. (2017). Zinc in Wound Healing Modulation. Nutrients. 10. 16. 10.3390/nu10010016.
DATCG,
Thanks for the link to the interesting video.
Here’s another video:
https://www.youtube.com/embed/wqdlET1_SQM
Background
TRIM25 is a novel RNA-binding protein and a member of the Tripartite Motif (TRIM) family of E3 ubiquitin ligases, which plays a pivotal role in the innate immune response. However, there is scarce knowledge about its RNA-related roles in cell biology. Furthermore, its RNA-binding domain has not been characterized.
Results
Here, we reveal that the RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain, which we postulate to be a novel RNA-binding domain. Using CLIP-seq and SILAC-based co-immunoprecipitation assays, we uncover TRIM25’s endogenous RNA targets and protein binding partners. We demonstrate that TRIM25 controls the levels of Zinc Finger Antiviral Protein (ZAP). Finally, we show that the RNA-binding activity of TRIM25 is important for its ubiquitin ligase activity towards itself (autoubiquitination) and its physiologically relevant target ZAP.
Conclusions
Our results suggest that many other proteins with the PRY/SPRY domain could have yet uncharacterized RNA-binding potential. Together, our data reveal new insights into the molecular roles and characteristics of RNA-binding E3 ubiquitin ligases and demonstrate that RNA could be an essential factor in their enzymatic activity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-017-0444-9) contains supplementary material, which is available to authorized users.
Choudhury, Nila & Heikel, Gregory & Trubitsyna, Maryia & Kubik, Peter & Nowak, Jakub & Webb, Shaun & Granneman, Sander & Spanos, Christos & Rappsilber, Juri & Castello, Alfredo & Michlewski, Gracjan. (2017). RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC Biology. 15. 10.1186/s12915-017-0444-9.
RNA-binding proteins (RBPs) are typically thought of as proteins that bind RNA through one or multiple globular RNA-binding domains (RBDs) and change the fate or function of the bound RNAs. Several hundred such RBPs have been discovered and investigated over the years. Recent proteome-wide studies have more than doubled the number of proteins implicated in RNA binding and uncovered hundreds of additional RBPs lacking conventional RBDs. In this Review, we discuss these new RBPs and the emerging understanding of their unexpected modes of RNA binding, which can be mediated by intrinsically disordered regions, protein–protein interaction interfaces and enzymatic cores, among others. We also discuss the RNA targets and molecular and cellular functions of the new RBPs, as well as the possibility that some RBPs may be regulated by RNA rather than regulate RNA.
W. Hentze, Matthias & Castello, Alfredo & Schwarzl, Thomas & Preiss, Thomas. (2018). A brave new world of RNA-binding proteins. Nature Reviews Molecular Cell Biology. 10.1038/nrm.2017.130.
DATCG at #117:
Beautiful video, than you.
OK, I suppose we must accept the nomenclature as it is, but your proposals are very good. I would definitely like “Intrinsically Flexible Proteins”! 🙂
My interest for Intrinsically Disordered, Proteins, and in particular Intrinsically Disordered regions, started some time ago with my interest in Transcription Factors.
Indeed, testing TFs for their evolutionary conservation, I realized that most of them can easily be considered as the sum of two components:
1) One (or more) DNA binding region: this is the domain part, which is almost always highly conserved, and shared between many different TFs.
2) One (or more) region, often much longer than the DNA binding region, where no recognizable domains can usally be found. This part has variable evolutionary conservation.
IOWs, this is more or less the same pattern we observe in E3 ligases, and in many regulatory proteins, while in traditional “effector” proteins we can usually observe a more striking prevalence of recognizable domains.
In TFs, moreover, this pattern is remarkably constant.
So, it is perfectly reasonable to assume that the “non domain” part is the one important in regulation issues, and in particular in flexible protein-protein interactions.
This was the idea behind my first OPs about information jumps, where I focused on Prickle1 protein, showing that the the “non domain” part was the one with the big information jump in vertebrates:
https://uncommondescent.com/intelligent-design/homologies-differences-and-information-jumps/
and that the “non domain part” was highly but differentially conserved in different groups of animals, as consistent with different and specific funations:
https://uncommondescent.com/intelligent-design/information-jumps-again-some-more-facts-and-thoughts-about-prickle-1-and-taxonomically-restricted-genes/
It seems that my ideas about “non domain” parts, which of course are usually called now “Intrinsically Disordered Regions”, has become rather fashionable.
For example, this recent enough paper seems to be exactly about that concept as applied to TFs:
Targeting protein-protein interactions (PPIs) of transcription factors: Challenges of intrinsically disordered proteins (IDPs) and regions (IDRs).
https://www.sciencedirect.com/science/article/pii/S0079610715000796?via%3Dihub
Unfortunately, it is not public access, and I could not access the full text, but the brief abstract is already telling:
Dionisio, DATCG, Upright Biped:
I have just found this very, very interesting and very recent paper. It seems to add beautifully to the ideas expressed in my previous comment at #123:
Evidence for a Strong Correlation Between Transcription Factor Protein Disorder and Organismic Complexity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434936/
And it is public access! 🙂
(Emphasis mine)
Beautiful, isn’t it? 🙂
I have not time now, but I will come back on that later.
Dionisio, DATCG, Upright Biped:
This is one of the first important papers about the relationship between TFs and IDR:
Intrinsic disorder in transcription factors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538555/#FN2
(Public access)
Dionisio, DATCG, Upright Biped:
Here is the Wikipedia page about IDPs:
https://en.wikipedia.org/wiki/Intrinsically_disordered_proteins
A few brief quotes:
Let’s remember that BRCA1 is a RING E3 ligase 1863 AAs long. The RING domain is located at the N terminus, and is abou 50 AAs long. Near the C terminus two BRCT domains, about 70 AAs each, can be recognized, and in the middle BLAST identifies a serine rich BRCT associated domain of about 150 AAs.
All the rest is “domainless”. We have a shorter N terminus sequence of almost 300 AAs, and a very long C terminus sequence of about 1150 AAs. No recognized domains in those two sequences!
Now, while a traditional approach to protein function would mainly emphasize the role of the domains, which is certainly very important, the new approach based on recognition of IDRs would probably try to understand the possible relational roles of the two longer sequences.
Here’s a list of papers referenced in this OP:
Burroughs, A. Maxwell, Lakshminarayan M. Iyer, and L. Aravind. “Structure and Evolution of Ubiquitin and Ubiquitin-Related Domains.” In Ubiquitin Family Modifiers and the Proteasome, edited by R. Jürgen Dohmen and Martin Scheffner, 832:15–63. Totowa, NJ: Humana Press, 2012. https://doi.org/10.1007/978-1-61779-474-2_2.
Chen, N., S. Balasenthil, J. Reuther, A. Frayna, Y. Wang, D. S. Chandler, L. V. Abruzzo, et al. “DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF- -Driven Epithelial-Mesenchymal Transition.” Cancer Discovery 3, no. 10 (October 1, 2013): 1172–89. https://doi.org/10.1158/2159-8290.CD-12-0499.
Chen, Zhijian J. “Ubiquitin Signalling in the NF-?B Pathway.” Nature Cell Biology 7, no. 8 (August 2005): 758–65. https://doi.org/10.1038/ncb0805-758.
Chen, Zhijian J., and Lijun J. Sun. “Nonproteolytic Functions of Ubiquitin in Cell Signaling.” Molecular Cell 33, no. 3 (February 2009): 275–86. https://doi.org/10.1016/j.molcel.2009.01.014.
Collins, Patricia, Izaskun Mitxitorena, and Ruaidhrí Carmody. “The Ubiquitination of NF-?B Subunits in the Control of Transcription.” Cells 5, no. 4 (May 12, 2016): 23. https://doi.org/10.3390/cells5020023.
Finley, D., H. D. Ulrich, T. Sommer, and P. Kaiser. “The Ubiquitin-Proteasome System of Saccharomyces Cerevisiae.” Genetics 192, no. 2 (October 1, 2012): 319–60. https://doi.org/10.1534/genetics.112.140467.
Komander, David, and Michael Rape. “The Ubiquitin Code.” Annual Review of Biochemistry 81, no. 1 (July 7, 2012): 203–29. https://doi.org/10.1146/annurev-biochem-060310-170328.
Kwon, Yong Tae, and Aaron Ciechanover. “The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy.” Trends in Biochemical Sciences 42, no. 11 (November 2017): 873–86. https://doi.org/10.1016/j.tibs.2017.09.002.
Morreale, Francesca Ester, and Helen Walden. “Types of Ubiquitin Ligases.” Cell 165, no. 1 (March 2016): 248–248.e1. https://doi.org/10.1016/j.cell.2016.03.003.
Stewart, Mikaela D, Tobias Ritterhoff, Rachel E Klevit, and Peter S Brzovic. “E2 Enzymes: More than Just Middle Men.” Cell Research 26, no. 4 (April 2016): 423–40. https://doi.org/10.1038/cr.2016.35.
Sun, Shao-Cong. “Non-Canonical NF-?B Signaling Pathway.” Cell Research 21, no. 1 (January 2011): 71–85. https://doi.org/10.1038/cr.2010.177.
Uchil, P. D., A. Hinz, S. Siegel, A. Coenen-Stass, T. Pertel, J. Luban, and W. Mothes. “TRIM Protein-Mediated Regulation of Inflammatory and Innate Immune Signaling and Its Association with Antiretroviral Activity.” Journal of Virology 87, no. 1 (January 1, 2013): 257–72. https://doi.org/10.1128/JVI.01804-12.
Veen, Annemarthe G. van der, and Hidde L. Ploegh. “Ubiquitin-Like Proteins.” Annual Review of Biochemistry 81, no. 1 (July 7, 2012): 323–57. https://doi.org/10.1146/annurev-biochem-093010-153308.
Zhang, Xiaofei, Arne H. Smits, Gabrielle B.A. van Tilburg, Pascal W.T.C. Jansen, Matthew M. Makowski, Huib Ovaa, and Michiel Vermeulen. “An Interaction Landscape of Ubiquitin Signaling.” Molecular Cell 65, no. 5 (March 2017): 941–955.e8. https://doi.org/10.1016/j.molcel.2017.01.004.
Please, correct any inaccuracies or omissions in the above list. Thanks.
Please, note that the above list does not include papers referenced in the comments.
Dionisio, DATCG, Upright Biped:
I would like to spend a few words about a concept which, while implicit in the many things we have said, has not been explicitly touched, neither in the OP nor in the discussion: the irreducible complexity of the Ubiquitin System.
Now, I think that it is an irreducible complexity of a very particular form.
Indeed, while we could certainly affirm an irreducible complexity of the whole system, I want to focus here on a very interesting aspect:
The Ubiquitin System, as we have seen, can be considered as the sum of hundreds, maybe thousands, of specific sub-systems. And each one of them is irreducibly complex.
I will try to be more clear.
Each functional sub-system can be considered as formed, at least, by:
1) Ubiquitin, or some ubiquitin-like protein
2) An E1 enzyme
3) An E2 enzyme
4) An E3 ligase
5) A target protein (the substrate of ubiquitination)
6) Usually, one or more deubiquitinating enzyme
7) Some ubiquitin interactor, recognizing the signal
8) Some final effector system, or protein, implementing the desired outcome
These components are more or less always present in each sub-system, even if sometimes some of them can be joined in one structure or protein. For example, in the proteasome the signal recognition and the effector are both part of the same structure, but of different parts of it. And there are rare cases of proteins that are at the same time E2 and E3 enzymes.
Now, it is rather clear that some parts are shared between some or all the subsystems.
Ubiquitin, for example, is the same in almost all of them (except when its role is implemented by ubiquitin-like proteins).
And the E1 enzyme is almost always the same (there are only a couple of forms of it).
The E2 enzymes are already more varied (about 40 of them), but for the moment we can consider them as mainly shared, for the sake of simplicity.
So, what is it that defines each individual sub-system?
The answer is easy enough: it’s the individual substrate, and its finale outcome.
Because, if we want to really define the function, we have to define it as follows:
The function of this system is to interact with this specific substrate X and direct it to the specific final outcome Y.
This function is different for each couple of X and Y.
But we know that there are thousands of different substrates which are ubiquinated, and we also know that at least some of them can be marked for different outcomes by the ubiquitin system.
So, it is not an overstatement to say that there are thousands of individual sub-systems in the ubiquitin system, each of them with a specific function, different from the function of all the others, because defined by a different couple of X and Y.
Of course, much of that diversification (but not all) is implemented by the fundamental role of E3 ligases, of which we have more than 600 different forms.
So, even if we reason only in terms of the characterizing E3 ligase (which is certainly reductive, but at least is simple), we have hundreds of different functional sub-systems, each of them defined by:
a) A specific substrate (which indeed is the object on which the system works, rather than a part of it)
b) A specific E3 ligase
c) A specific symbolic signal (generated by the interaction of a and b)
d) A specific outcome
OK? Now comes the interesting part:
Each of those sub-systems, even if it shares parts with the other sub-systems (for example the E1 enzyme or the proteasome), is in itself irreducibly complex.
Why?
Because it would have no function at all if all the parts we have listed were not present, and it would have no function at all if even one of the specific parts, in particular the specific E3 ligase, were not present.
IOWs, the system is irreducibly complex because no single part of it can be discarded, in the core form we have described. And that irreducible complexity is different for each subsystem, because at least one part (the E3 ligase) is absolutely specific, and cannot be discarded at all. Because it’s the E3 ligase that recognizes the specific Y, and knows what signal is appropriate for it.
Of course, many other factors can contribute to the unicity of each sub-system. For example, even if one E3 ligase can deal with many different substrates, it is perfectly reasonable that a specific combination of E1, E2, E3, signal, deubiquinating enzyme and outcome is usually unique for most substrates. That would make thousands of unique irreducibly complex sub-systems, rather than “only” hundreds.
So, while the Ubiquitin System is, as stated in the OP and analyzed in detail in the discussion, a wonderful example where functional complexity and semiosis are joined, it is equally true that we can extend that statement to the third outstanding feature of complex designed systems, and say that:
The Ubiquitin System is a wonderful example of a system where functional complexity, semiosis and irreducible complexity are joined together.
Dionisio at #121 and 122:
This is another completely new aspect, and discovered very recently, it seems. Thank you for finding that! You are, as usual, a very good digger. 🙂
Of course, RNA could not be missing form the many-faceted world of ubiquitin regulation. In the end, RNA is probably the key crossroad where all regulatory networks do join. I suppose that Arthur Hunt would agree on that! 🙂
TRIM25 seems to be a very busy actor too. From Uniprot:
gpuccio @129:
Actors in Hollywood would dream of having at least a fraction of the roles TRIM25 seems to perform according to the information you quoted. 🙂
Ubiquitin could collect Oscars in a warehouse. 🙂
However, ironically ubiquitin is not a celebrity according to the mainstream media. Not yet.
BTW, you mentioned professor Arthur Hunt. Any news from him? Did he ever come back to continue the discussion on the spliceosome?
gpuccio,
FYI – The list @127 was produced using Zotero.
However, if I were to stick to the neo-Darwinian style, I would have to say that it was produced by Zotero, which implies that the software decided how, where and when to produce that list.
🙂
Dionisio:
No, no news from Arthur Hunt.
However, I would say that his “presence” seems to linger among us! 🙂
It seems to be a good strategy: gives just a little of yourself, and you will be sorely missed. 🙂
Dionisio:
Zotero seems an useful tool. I will try it.
Do you think it is a designed object? 🙂
Dionisio, DATCG, Upright Biped:
Hey, we have almost forgotten apoptosis! 🙂
Fortunately, here is a brand new paper on that subject:
Delineating Crosstalk Mechanisms of the Ubiquitin Proteasome System That Regulate Apoptosis
https://www.frontiersin.org/articles/10.3389/fcell.2018.00011/full
(Public access)
Emphasis mine.
“Around 100 enzymes” from the Ubiquitn System, just to regulate Apoptosis? Not bad, I would say.
“Fine tune”? You bet!
By the way, Figures 3,4, 5 and 6 (and their respective legends) are some more fun for the lovers of simplicity! 🙂
And Tables 1, 2, 3, 4, 5, 6, 7 and 8 are a very good list of the ubiquinitating and deubiquinating enzymes involved in this “simple” regulation network.
But, of course, RV and NS can easily explain all that. No need to take part in such a trivial discussion…
Dionisio, DATCG, Upright Biped:
Just a quick update of the list at #90:
A brief list of the cellular processes we have touched in the OP and discussion, all of them deeply connected to the Ubiquitin System network:
a) Proteasome degradation
b) Autophagic degradation
c) Mitophagy
d) Cell signaling and transmission pathways
e) Double-Strand Breaks DNA repair
f) Neuronal regulation
g) Regulation of innate immunity
h) Regulation of adaptive immunity
i) Regulation of T cell and B cell differentiation
j) RNA interactions
k) Apoptosis
OK, I am sure we are going to add new ones, if we keep digging. 🙂
Dionisio, DATCG, Upright Biped:
We have seen the role of ubiquitin system in histone ubiquitination, especially in DNA repair.
But what about DNA methylation, probably the first and foremost epigenetic mechanism?
Another brand new paper:
Structural and mechanistic insights into UHRF1-mediated DNMT1 activation in the maintenance DNA
https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gky104/4870013
DNMT1, DNA (cytosine-5)-methyltransferase 1, is a key enzyme in DNA methylation, and many other things. From Uniprot:
Dionisio, DATCG, Upright Biped:
What about early embryo development?
Embryonic lethality in mice lacking Trim59 due to impaired gastrulation development.
https://www.nature.com/articles/s41419-018-0370-y
(Public access)
Emphasis mine.
TRIM59 is a RING E3 ligase. This is apparently a new functional specificity, because the Uniprot page function section states simply:
“May serve as a multifunctional regulator for innate immune signaling pathways.”
Dionisio, DATCG, Upright Biped:
Embryonic stem cells are certainly an extremely hot subject.
This too is brand new:
Cellular functions of stem cell factors mediated by the ubiquitin–proteasome system
https://link.springer.com/article/10.1007%2Fs00018-018-2770-7
(Paywall)
#123 Gpuccio,
Oh joy 🙂 haha, more reading! I briefly looked at your first link OP on Information Jump that started all of this. Briefly looked through it and read the epic take down in your comment at #138 of Alicia’s selective blast. Ha!
OK, looks like more OPs to read. Thanks for sharing those links. I’ll catch up over time to gain more perspective.
#112 Dionisio
Agree, and a belief in blind, unguided orthodoxy.
It may be why Systems Biologist and Systems based approaches in molecular sciences have recognized the lack of answers and are more willing to open up discussions on failure of neo-Darwinism to address known problems.
Eventually science must move ahead, be it Darwin dead or neo-Darwinism being pushed aside too as a weak explanation.
GP,
10 days and 140 comments, not a critic in sight. Congratulations.
You should be feeling good about that.
🙂
#123 Gpuccio,
1st, thanks for playing along with my nomenclature mini-rant
😉 Alas, no renaming of IDP, IDR.
I guess I see IDPs as flexible-ordered 3D states. A bit like a rubic cube but in a combinatorial process that recognizes a match or is stimulated and folds upon binding sites.
Or another analogy, a universal socket or universal wrench that adjust based upon conditional sizes of bolts.
In case of IDPs, their flexibly adjustable so-to-speak to a binding site of multiple substrates
Disorder represents a randomness to it, even if it’s used in contrast to normal folding or “normal” regions. Whatever is normal per say in a random world of natural selection?
If by Design, then there’s a reason for this open pattern, 3D free structure and so-called disordered regions.
Came across another paper re: IDPs, IDRs and folding, partial-fold, conditional-folds, etc.
Mosaic nature of the protein structure–function space: functional foldons, semi-foldons, inducible foldons, nonfoldons and unfoldons
and more…
There’s a reason for nonhomogeneous distinction and long length of disordered regions. And tails being more disordered as well. What yet I do not know, but if by design there is.
This paper notes that IDPs IDPTs IDRs are complimentary to “ordered” proteins.
and more… environmental factors 🙂
Who knew disorder could be functional? 😉
oops, wrong link in #142, Should be…
Mosaic nature of the protein structure–function space: functional foldons, semi-foldons, inducible foldons, nonfoldons and unfoldons…
http://www.pnas.org/content/111/43/15420.full
.
I wonder if his graphic is entirely accurate though…
Fig 1 Functional roles of transiently and intrinsically disordered regions within proteins Circle of
.
Try this one last time, for link at #142…
Yay…
Functional roles of transiently and intrinsically disordered regions within proteins
http://onlinelibrary.wiley.com.....13202/full
Gpuccio @126
re: BRCA1
Enjoying reading FEBS Journal by FEBSPress on the subject
you expanded upon. Don’t remember coming across this journal in the past.
re: your comments…
Yep, long sequences.
That’s interesting, 1481AAs from paper below in 2014
on BRCA1 …
BRCA1, A ‘Complex’ Protein Involved in the Maintenance of Genomic Stability – 2014
~1481AAs = “…no Domain structure and is predicted to be intrinsically disordered…”
So it is a “type of protein structure” Just not rigid folding angles of “noraml” proteins so they named it disordered, instead of the Flexible aspect, or Conditional activity of folding. Or Induced, etc. Though I agree Gpuccio, Flexible includes all folds and activity.
But can they make up their minds? “Type of Structure,” no
structure? Unstructural? 😉
I digress, onward…
* , () emphasis mine
There’s some info on N-Terminus…
.
And kind of funny, came across Douglas Axe posting on Conditional Folding! 🙂
I’m not the only one stuck on meaningful nomanclature. Plus great stuff on IDPs! And good response to Venema.
That’s great stuff by Axe! And a good take down of Venema’s lazy reading of a research paper.
Axe’s response to an upcoming critique and response to his Book …
Losing the Forest by Fixating on the Trees — A Response to Venema’s Critique of Undeniable
.
Upright Biped:
“10 days and 140 comments, not a critic in sight. Congratulations.
You should be feeling good about that.”
Maybe I should. But I miss the fight! 🙂
DATCG just mentioned Alicia Cartelli, and, believe it or not, I felt a pang of nostalgia! 🙂
Understood.
…but still.
🙂 🙂 🙂
DATCG:
“Who knew disorder could be functional?”
Thank you for the link.
“Functional roles of transiently and intrinsically disordered regions within proteins”
Very interesting indeed.
So, folding and unfolding can be considered as a continuum, a space of functional potentialities which is differently structured in different proteins and protein regions. Fascinating.
I thin the concept here is not so much of “disorder”, but rather of “absence of a rigid, or prevailing, modality of folding”.
This is a very interesting point. Indeed, functional specification has little to do with order. Functional sequences are often more pseudo-random than pseudo-ordered. That’s one important reason why functional complexity can never arise from necessity laws, which by definition are defined by regularities.
Secondary structure is probably more tractable and more similar to some form of “order”, but tertiary structure can scarcely be predicted with our resources.
A functional sequence which eludes both secondary structures and rigid tertiary structures is even more interesting, because it seems to be pure function with really negligible “order”. In that sense, it is an even more amazing object of design.
A scenario of incredible functional flexibility and complexity is daily emerging from the new biology. It’s not surprising that out kind interlocutors don’t seem too keen to discuss it! 🙂
DATCG at #147:
Axe is one of the best! 🙂
By the way, I am reading his “Undeniable”. I will probably write something about it when I am finished.
He says:
“Moreover, anyone who reads this review paper with open eyes will see that conditional folding is in fact a remarkable design feature.”
Of course, he is absolutely right! The function of IDPs and IDRs (however we call them) screams design even more than the traditional function of well understood domain proteins!
Gpuccio #150
Yes! Thanks for summing it up nicely. 🙂
Functional Potential, conditional, induced or not. The “Flexibility” of the structure allows it.
There’s a place for both Rigid enforcement of angles and flexible IDPs based on Systems
Requirement, Surroundings or function specificity – Purpose.
Yes 🙂 Again, thanks for simplifying with a good summary! It’s common sense.
But it’s hard to use common sense from a Darwin perspective. They must use convoluted reasoning, avoidance of certain terms to get around, jump-over and slide-under Design in Life to embrace unguided blind random events.
What’s funny is even if they carefully self-govern or by incompetence use language that keeps out Design principles, it inevitably creeps back in because even the most ardent Darwinist have a slip of the tongue. A rotor’s a rotor and not by accident.
We know there’s differences between Random, Ordered and Organized Function(see Abel, Trevors;
Three Subsets of Sequence Complexity: Random, Ordered and Functional… Theorectical Biology)
Where: Functional = Organized Code
Which brings us back to your point on Semiosis and UB’s contributions on the subject.
What is information? How is it represented and communicated? Different Types and Category?
This is where Darwinist usually dismiss these areas based on definitions and inability to measure precisely Organized, Sybmolic, Informational Content, etc. There’s been many good post on this here at UD.
But they continue to miss the entire point. It’s Code! 🙂 And Code is well known, common sense sign of Design. Not of random process, certainly not ordered patterns.
Hopefully new technology will allow scientist to look deeper and through time as flexible folds are captured during binding or unfolding and release. I thought the NMR
video captured the difficulty you mention quite well.
Organized Functionality 🙂 Sequences and structure may appear “disordered” but they’re highly organized, not random. With intent of flexible functionality. Screams Design.
And as the paper by Abel, Trevors points out, “Functional Sequence Complexity is invariably associated with all forms of complex biofunction…,”
Whereas “No empirical evidence exist of either Random Sequences or Ordered Sequences having produced a single instance of sophisticated biological organization.”
“Organization… manifest Functional Sequence Complexity, rather than Random Events(RSC) or low-informational self-ordering phenomena(OSC).”
Random does not, Ordered does not. Symbolic Organization does via Design.
right! 🙂 You’ve put together another well thought out post. Thanks for your patience as well in these discussions.
Really have enjoyed these post.
.
#152 Gpuccio
re: Axe
As Axe stated, most people get Design intuitively. That was a
great read, his article that is 🙂 He mops up the floor with Venema.
I’ve not purchased Undeniable yet, but will. Have read Meyers
Signals in the Cell which I thoroughly enjoyed. Still need to get through Darwin’s Doubt. Look forward to Axe’s book.
How do you like it so far? Not to give away your Book Review, , but what is a highlight of the book to you?
.
Just to mention once again Gpuccio.
So, I’d kinda went on a mini-rant about terms. But had not read Axe. Then, when I came across Axe’s comments in that article. it made me realize I was not alone in my frustration and if an expert scientist like him sees this, it made me feel like I was on the right track.
Terms matter and Darwinist are always choosing which are standardized into our vocabulary of genetics, molecular biology, etc. Then children are indoctrinated to it. If I could, I’d rewrite so much of it, lol.
Like an entire Architectural Design Initiative to free minds of the blind, and open their eyes to Design.
It would be a massive undertaking of course. But what if, instead of Latin, instead of indoctrinated language of blind, unguided process, we could rewrite Life’s processes by Design Code Logic and nomemclature?
Just a wild thought. In the approach of an Open Code of Life, so to speak. There’s closed platforms like Apple and Microsoft, then there is Linux and solutions like WordPress, etc, many open architectures where developers around the world contribute.
Kids and young people pick up on it fast, very fast.
I think sometimes, the past holds us back. By restricting thought to ancient languages and antiquated ideas(Darwinism), the specialist keep a closed platform. Many of these specialist are great documenters, collectors and categorizers, but many are not innovators or creatives. Not to say we do not need such specializations, but often times I think the barriers are artificially high due to past historical norms.
We need to open it up. Open up the Codes of Life to innovators and creative people.
For readers, Video and explanations of Protein Structures…
Primary, secondary and tertiary…
https://www.khanacademy.org/science/biology/macromolecules/proteins-and-amino-acids/v/tertiary-structure-of-proteins
FYI, has anyone seen Abel’s paper from 2015?
off-topic: PDF Document…
Functional Sequence Complexity (FSC) Measured in Fits(Functional bits)
.
Back on topic, Durston, Wong, Chiu, Li paper(2012)…
Statistical Discovery of Site inter-dependencies in Sub-molecular Hierarchical Protein Structuring
Partial Background
Results
Conclusions:
Section on Classifying the Structures
DATCG at #153:
I am still at the beginning of Undeniable, too early to say something, except that it seems well written and interesting.
DATCG at #152:
Thank you for quoting Abel and Trevors, and their fundamental paper.
I think that Abel and his co-workers have given us some very clear and basic intuitions, that still remains as foundations of ID. I am paticularly in debt to Abel for many important concepts, like the three types if sequence complexity, the difference between descriptive information and prescriptive information, the idea of “configurable switches” and so on.
Durston is another important contributor to ID thought. He has been the first to propose a real method to measure functional information in proteins:
Measuring the functional sequence complexity of proteins
https://tbiomed.biomedcentral.com/articles/10.1186/1742-4682-4-47
While my approach, based on sequence conservation, is slightly different, the basic idea is the same.
I did not know Durtson’s paper on ubiquitin, that you quote at #157. I will read it with great interest! 🙂
The same is true for Abel’s paper from 2015 that you reference at #156. I hope to comment on that too, as soon as possible. 🙂
Thank you for your precious contributions!
Exosome relation with ubiquitin regulation of platelets.
Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro-atherothombotic cellular functions
Authors: S. Srikanthan, W. Li, R. L. Silverstein, T. M. McIntyre
First published: 13 October 2014
Gpuccio #159
The day I first came across Abel and Trevors paper; Three Subsets…, was eye-opening in understanding the deception of Darwinism not recognizing Organization as Design principle.
I read through it again and again. And probably need to refresh after so long.
I agree, they’re contributions are foundational and clear away old Darwinian concepts or deceptions to muddy the water between Order and Organization.
And yes, Durston 🙂 So I’m curious what you think of Abel’s FITS paper. Look forward to it!
The Null Hypothesis they set forth I don’t think has been challenged? But it’s been some time.
I wonder if any of day to day commenters her at UD are willing to give it a go in attempt to falsify Abel and Trevors’ challenge. That would make for an interesting post?
Have a good day/evening.
DATCG at #160:
Amazing. So, we can add cell to cell communication to the processes where ubiquitin is directly involved!
Gpuccio #162
thought you might like that 🙂
DATCG:
I have read the Durston paper linked at #157, Very interesting.
Durston is certainly going on finding beautiful ways to analyze protein sequences for specific patterns.
His guiding principle is, as always, functional information. And therefore he founds his measures upon sequence conservation. And that is great!
In this paper, he is focusing not on traditional functional information, but on functional information related to aminoacid site interdependency. He has developed a complex and brilliant bioinformatics algorithm to do that.
The results seem very good, because the algorithm seems capable of identifying functionally related subunits just by analyzing sequences and their conservation, and those results correspond very well to what is known from structural studies.
This is a wonderful demonstration of how focuisng on functional information can yield important results and be a new sensitive tool to understand the complex world of protein function.
That’s why the reluctance of the neo-darwinist academy to even consider functional information as a real and tangible and measurable entity is a serious science stopper.
This is a good example of cognitive bias, and of how a wrong ideological approach can make scientists blind to obvious avenues of research.
It is not a case, of course, that Durston (and, probably, his co-workers) come from the ID field! 🙂
DATCG:
By the way, it’s also not a case, I believe, that he is using ubiquitn as the main testing molecule for his method. That certainly confirms not only the huge amount of functional information in its sequence, but also the complex and nuanced aspects of its biophysics profile.
DATCG:
I have read Abel’s “Fits” paper, referenced by you at #156.
It is a very good summary of his thought, and of his personal contributions to ID theory.
I absolutely agree with Abel’s ideas. They are clear and undeniable.
I would like to explain here the only two points that I usually need to add in my discussions about my personal model of ID. They are in no way in contradiction with Abel’s discourse, but they are not usually explicit in his reasoning, at least as far as I can say.
1) The first is that the role of consciousness is not made explicit. It is clearly implicit, for example here:
Emphasis mine.
Or here:
We can see here a strange pattern that is often seen in design literature. There is a constant reference to ideas like choice, or agency, but they are not explicitly defined.
The same is usually true for design itself: strange as it seems, it is usually not defined in ID literature.
I have always felt that as a rpoblem, so the first OP I have published here was dedicated to:
Defining design.
https://uncommondescent.com/intelligent-design/defining-design/
And here is my definition:
I think that it is not possible to define “agency” or simply “design” without referring to conscious states.
The reason is simple: conscious experiences are observable facts, and therefore have intrinsic scientific validity, while “agency”, “choice”, or even “design” are concepts, and need to be defined in terms of observable fatcs to be used in science.
So, I define design in terms of conscious experiences (experience of meaning and of purpose) that are at the origin of the form outputted into material objects. That is an empirical and universal definition.
2) The second point is that we need to set a quantitative threshold to functional complexity to use it to infer design.
The reason is simple: if we want to allow for any definition of function (which I do in all my reasonings), we must acknoledge that very simple functions do exist.
Now, very simple functions can be implemented by a few bits of information, and a few bits of information can certainly arise by random events.
IOWs, a cloud can resemble a weasel, if the resemblance is not so strict that a lot of specific bits are involved.
So, it is true, as Abel says, that:
(Emphasis mine)
It’s absolutyely true! The only problem is that “sophisticated” is too vague.
In science, we need an objective and possibly quantitative way to decide what is “sophisticated” and what is not.
A quantitative approach is to define functional information as “complex” by an appropriate threshold. Usually, 500 bits are more than enough for any physical system in the universe. Realistically, much less is enough.
A qualitative approach can be to assess semiosis, the presence of symbolic codes. Those structures are “qualitatively” beyond the reach of non conscious systems.
The beauty of the Ubiquitin Systems is that it includes, in huge amounts, both those features: Functional Complexiy in the order of thousands or millions of bits, and undeniable and rich Semiosis.
And, as I have argued at #128, Irreducible Complexity too. Tons of it! 🙂
DATCG @160, gpuccio @162:
Is this related?
Gupta, Nilaksh & Li, Wei & Mcintyre, Thomas. (2015). Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and Thrombosis. Arteriosclerosis, thrombosis, and vascular biology. 35. 10.1161/ATVBAHA.115.306054.
Objective:
Platelets express a functional ubiquitin-proteasome system. Mass spectrometry shows that platelets contain several deubiquitinases, but whether these are functional, modulate the proteome, or affect platelet reactivity are unknown.
Approach and results:
Platelet lysates contained ubiquitin-protein deubiquitinase activity hydrolyzing both Lys48 and Lys63 polyubiquitin conjugates that was suppressed by the chemically unrelated deubiquitinase inhibitors PYR41 and PR619. These inhibitors acutely and markedly increased monoubiquitination and polyubiquitination of the proteome of resting platelets. PYR41 (intravenous, 15 minutes) significantly impaired occlusive thrombosis in FeCl3-damaged carotid arteries, and deubiquitinase inhibition reduced platelet adhesion and retention during high shear flow of whole blood through microfluidic chambers coated with collagen. Total internal reflection microscopy showed that adhesion and spreading in the absence of flow were strongly curtailed by these inhibitors with failure of stable process extension and reduced the retraction of formed clots. Deubiquitinase inhibition also sharply reduced homotypic platelet aggregation in response to not only the incomplete agonists ADP and collagen acting through glycoprotein VI but also to the complete agonist thrombin. Suppressed aggregation was accompanied by curtailed procaspase activating compound-1 binding to activated IIb/IIIa and inhibition of P-selectin translocation to the platelet surface. Deubiquitinase inhibition abolished the agonist-induced spike in intracellular calcium, suppressed Akt phosphorylation, and reduced agonist-stimulated phosphatase and tensin homolog phosphatase phosphorylation. Platelets express the proteasome-associated deubiquitinases USP14 and UCHL5, and selective inhibition of these enzymes by b-AP15 reproduced the inhibitory effect of the general deubiquitinase inhibitors on ex vivo platelet function.
Conclusions:
Remodeling of the ubiquitinated platelet proteome by deubiquitinases promotes agonist-stimulated intracellular signal transduction and platelet responsiveness.
Mukherjee, Rukmini & Das, Aneesha & Chakrabarti, Saikat & Chakrabarti, Oishee. (2017). Calcium dependent regulation of protein ubiquitination – Interplay between E3 ligases and calcium binding proteins. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 1864. 10.1016/j.bbamcr.2017.03.001.
The ubiquitination status of proteins and intracellular calcium levels are two factors which keep changing inside any living cell. These two events appear to be independent of each other but recent experimental evidences show that ubiquitination of cellular proteins are influenced by calcium, Calmodulin, Calmodulin-dependent kinase II and other proteins of calcium dependent pathways. E3 ligases like Nedd4, SCF complex, APC, GP78 and ITCH are important regulators of calcium mediated processes. A bioinformatics analysis to inspect sequences and interacting partners of 242 candidate E3 ligases show the presence of calcium and/or Calmodulin binding motifs/domains within their sequences. Building a protein-protein interaction (PPI) network of human E3 ligase proteins identifies Ca2 + related proteins as direct interacting partners of E3 ligases. Review of literature, analysis of E3 ligase sequences and their interactome suggests an interconnectivity between calcium signaling and the overall UPS system, especially emphasizing that a subset of E3 ligases have importance in physiological pathways modulated by calcium.
Ubiquitin conjugation probed by inflammation in MDSC extracellular vesicles
R. Adams, Katherine & Chauhan, Sitara & B. Patel, Divya & K. Clements, Virginia & Wang, Yan & Jay, Steven & Edwards, Nathan & Ostrand-Rosenberg, S & Fenselau, Catherine. (2017). Ubiquitin conjugation probed by inflammation in MDSC extracellular vesicles. Journal of Proteome Research. 17. 10.1021/acs.jproteome.7b00585.
Ubiquitinated proteins carried by the extracellular vesicles (EV) released by myeloid-derived suppressor cells (MDSC) have been investigated using proteomic strategies to examine the effect of tumor-associated inflammation. EV were collected from MDSC directly following isolation from tumor-bearing mice with low and high inflammation. Among 1092 proteins (high inflammation) and 925 proteins (low inflammation) identified, more than 50 % were observed as ubiquitinated proteoforms. More than three ubiquitin-attachment sites were characterized per ubiquitinated protein, on average. Multiple ubiquitination sites were identified in the pro-inflammatory proteins S100 A8 and S100 A9 characteristic of MDSC, and in histones and transcription regulators, among other proteins. Spectral counting and pathway analysis suggests that ubiquitination occurs independently of inflammation. Some ubiquitinated proteins were shown to cause migration of MDSC, which has been previously connected with immune suppression and tumor progression. Finally, MDSC EV are found collectively to carry all the enzymes required to catalyze ubiquitination, and the hypothesis is presented that a portion of the ubiquitinated proteins are produced in situ. Spectral counting and pathway analysis applied to the total protein content of inflammatory and conventional MDSC EV reveals significant enrichment in the proteins of the neutrophil degranulation pathway with induced inflammation.
Dionisio @ 169: Please give me the simplified version of your comments 167 through 169. What is the main point you are making?
Ubiquitin everywhere:
http://www.jimmunol.org/search/ubiquitin
TWSYF @170:
Good question. Thanks for asking.
Those referenced papers add more evidences for this argument:
The known facts -not the unknown- definitely point to complex functionally specified informational complexity.
Dionisio at #167:
Paltelets are strange things. they are not really cells, but rather cell fragments. And yet, these small packages of cytoplasm are central in a lot of complex regulations involving the whole organism, especially coagulation and inflammation.
I am not surprised at all that ubiquitin is well represented in the platelet repertoire, and that it could have important functions both in the platelet itself, and in cell to cell communication.
Hematology has always been one of my favourite subjects in medicine! 🙂
Dionisio at #168:
Here again, no surprise. Calcium is one of the most important second messengers in cell signaling. It has fundamental roles in almost everything.
We have already seen that the ubiquitin system and cell signaling are as connected as one can imagine. 🙂
Truth Will Set You Free:
I think the main point could be:
We started with the idea that ubiquitin is really ubiquitous, but by digging and digging I would say that reality has greatly overcome our wildest imagination! 🙂
Dionisio #167-168 and 169
oh yes, good ones!
I agree with Gpuccio’s comments. Thanks for the papers.
And in posting the Journal of Immunology. Been a while since I looked directly at it. I usually stay buried at NCBI for searchers. Also Research Gate.
Great additions!
Gpuccio @164
Right, Agreed! The constant complaint by neo-darwinist is Design is a “science stopper,” but truth is Design is a great Science Starter.
How do we know this? By all the scientist before us who sought design and purpose of function in the past.
And modern day arguments of “junk” DNA. Design Theorist said we should find function in “junk” DNA. They did not predict all of it would be, but certainly more than neo-Darwinist who had written off “junk” DNA as leftover trash.
Design is the better heuristic going forward in the age of ENCODE and molecular processing systems. It takes systems analysis of the whole to reverse engineer the myriad of organized, synchronized components that dance together in the cell, across cells, across networks, organs and forms.
re: Durston, yes yes yes 🙂 It’s been years since I’ve ran Differential Equations through any kind of coding efforts, so I’m rusty on it. But I read his papers as well and was thrilled to see him tackle Function. I lurk here a lot, don’t usually comment to often at times. But always read anything from Durston, et al., and obviously post like yours 🙂
Gpuccio #165…
Durston’s, et al., Figure 2 Ubiquitin findings…
Cluster tree for ubiquitin.
The attribute clusters discovered from the aligned sequence data for the Ubiquitin family are shown above and organized vertically according to their order (the number of interdependent sites they contain). The organized clusters form primary branches, numbered 1 to 14 across the top of the figure. In each branch, the attribute cluster with the highest internal interdependency (highest SR(mode) value) was chosen as the representative cluster for that branch and is labeled according to its branch number. Two secondary clusters, discussed in the text, are labeled 12 s and 13 s. From this cluster tree, new insights can be gained into details of folding and structure.
Durston, continued…
Ubiquitin (A) 3D Structure using 1UBQ Solved Structure, (B) Module 1 Clusters, (C) Cluster 12 s, discovered by K-modes Algorithm
.
Durston, Wong, Li Chui, continued…
Graphic representation…
Fig 4 Secondary structure of ubiquitin with locations of modules and major clusters.
BTW re: David Abel,
While I’d followed most of his publshed papers, I did not know he had the following site:
Peer-reviewed publications of David L. Abel
More reading! 😉
Dionisio, DATCG, Upright Biped:
This is brand new (14 February 2018) about the possible connections between E3 ligases mutations and human neurological disorders:
A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders
gpuccio @182:
That paper just came out of the printing press!
The ink hasn’t dried out yet.
This reminds me of something you wrote @87:
Gpuccio @182,
oooooo… followed your paper link and found another by
same arthor, who responded to a question.
She recommended this link: UbiNet Not to be confused
with SkyNet 😉
UbiNet the Next Net frontier in Ubiquitin Services
Haha, seriously though. A site full of resources. Had not seen this.
from the site…
never know what you will find down the wabbit hole…
It has a lovely FUNCTION button to click on that leads you
to this page…
Functions Galore of Ubiquitin and Cool Categories to Choose from, including Cellular Process
Organ Development is one of them. Had we already added that to the UBQ List?
Also, MAP3K
Enjoy! 🙂
And thanks for the link on Neurological Disorders.
70 different types of neurological disorders. Wow!
I wonder in the future, how many diseases and disorders across the spectrum of the Genome is due to Epigenetic mutations? Which are deleterious to active configurations, passed down as a result of environmental queues or bad actions of the parent, for example like Fetal Alcohol Syndrome.
Or how the old saying goes, You Are What You Eat or Drink
.
#182 Dionisio,
Good day 🙂 Check out the UbiNet Link I posted above, then click Cellular Process Tab at top and voila…
organ morphogenesis
surely you jest, RM+NS solves everything! 😉
TWSYF @170:
Valid request. Thanks.
The best comments related to your valid request were written by GP @173-175 & DATCG @176.
DATCG @185:
Thank you for such a good information.
I’m glad you found that resource and shared it with us here right away. It seems like you’ve discovered a rich mine. Well done!
Have a good weekend.
This excellent 100% scientific thread -started and maintained by gpuccio with very helpful contributions by DATCG and other folks- seems to confirm the Big Data issue associated with Biology research lately. The overwhelming avalanche of data coming out of wet and dry labs seems to demand more multidisciplinary research teams working really hard to try figuring out how to understand all that information.
We ain’t seen nothin’ yet. The most fascinating discoveries are still ahead.
You too Dionisio!
Yeah, it really ties Ubiquitin and it’s impact altogether
in a neat, easy format.
I wonder if they’re using Durston’s, Wong, et al., K-mode algorithm. Hmmmm…
Dionisio @188,
And how much of the former “junk” has been fully explored yet?
I want to keep reminding people of Dan Graur’s epic meltdown…
“If ENCODE is right, evolution is wrong!”
I’m curious if anyone is tracking the artificial threshold he set on Epigenetic Function vs “JUNK”
Because anytime researchers find new function in previous areas thought to be junk, it opens new doors for more research in those new areas.
You’re so right… the future’s so bright, the Darwinist will have to wear Shades… on top of their Blinders.
DATCG @184:
The interesting resource you have found seems to be produced by this university:
UbiNet’s Team: Van-Nui Nguyen, Kai-Yao Huang, Prof. Tzong-Yi Lee, and Prof. K. Robert Lai: Department of Computer Science and Engineering, Yuan Ze University.
https://www.yzu.edu.tw/
Thanks for sharing your discovery right away.
I certainly can use it.
gpuccio,
I would like to read your assessment of the interesting resource found by DATCG.
No rush. Take your time.
Thanks.
TWSYF @170:
You may enjoy reading what DATCG just wrote @190:
“[…] the future’s so bright, the Darwinist will have to wear Shades… on top of their Blinders”
Really funny. DATCG has a healthy sense of humor.
DATCG at #184:
UbiNet! Great resource, thank you! 🙂
I am avidly exploring it.
It was great ofnyou to find it. I had looked for U3 ligases databases, but did not find it.
As usual, I like the general statistics a lot:
Ubiquitinated proteins 14,692
– Ubiquitination sites 43,948
E1 (activating enzyme) 2
E2 (conjugating enzyme) 46
E3 (ubiquitin ligase) 499
Protein-protein interaction 430,530
Domain-domain interaction 286,758
E3-associated functional category 2,143
Literatures 44,184
Emphasis mine.
So, it seems that our idea that most proteins undergo some ubiquitination, at some moment in their history, is not too wild!
Dionisio:
“That paper just came out of the printing press!
The ink hasn’t dried out yet.”
Then look at this one (1 March 2018):
Degradation for better survival? Role of ubiquitination in epithelial morphogenesis.
http://onlinelibrary.wiley.com.....4/abstract
(Paywall)
The paper is very good.
I would like to quote this passage which sums up some of the combinatorial potentialities of the ubiquitin system:
So, in brief, we have a potential of:
a) Over 50000 different permutations for the writing system
b) Millions of different permutations for the code itself
That’s quite a potential! 🙂
Dionisio:
Knowing your interests, I though you could like this part of the “Contents” section of the paper referenced at #195:
gpuccio @195,
You pulled that paper out of the printing press and got still-wet ink spilled all over! 🙂
And Wow! that’s quite a rich code!
Now, what determines which of those combinations is used where and when and for what so that things fit nicely?
Please, note that the tricky word ‘exactly’ is not in the above question so that it qualifies as honest. 🙂
Thanks.
gpuccio @196:
Yes, you thought it right: that’s a very interesting topic for me. Thank you for pointing to that paper.
Gpuccio,
Curious, which group of Proteins are NOT degraded, or tagged for destruction by Ubiquitin tagging?
Even as you pointed out, Apoptosis is at some point impacted by Ubiquitination processes.
Even if not by direct interaction, it appears 2nd, 3rd levels along the path can involve different forms of mono or poly-ubiquitin chains that guide or modify the pathway to eventual degradation or recyling, etc.
Am I going to far in contemplating, all Proteins may have some form of interaction? Either direct or at a distance with the Ubiquitin Code?
.
gpuccio @89:
For lovers of simplicity?
Yes, quite simple indeed:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490640/figure/F0003/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490640/figure/F0005/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490640/figure/F0006/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490640/figure/F0007/
UB @36, @42, @44, @94:
(Attn. DATCG @101 too)
It seems like both Barbieri and Pattee made some interesting and valid affirmations, but overall they still went off the tangent and drew the wrong conclusions.
I assume UB referred to this person:
http://binghamton.academia.edu/HowardPattee
Let me repeat a comment that was posted @21:
“This thread has too much bad news for the ‘modern synthesis’ and the ‘third way’ clubs.”
Dionisio:
I agree: interesting arguments, interesting discussions, and wrong conclusions.
Why?
That’s the only thing that can happen when intelligent and honest people start from some acritical assumption, which can never be questioned, even if it is not based on any evidence: so, all wrong consclusions in his reasonings simply derive from accepting as a dogma that evolution happened by the imaginary mechanisms of the neo-darwinian theory.
A wrong assumption is not only a science stopper: it is a thought stopper!
Dionisio:
“This thread has too much bad news for the ‘modern synthesis’ and the ‘third way’ clubs.”
Maybe. So, it seems they are definitely recurring to some Ostrich policy! 🙂
https://en.wikipedia.org/wiki/Ostrich_policy
gpuccio @133:
No, zotero is not a designed object.
That software resulted from a bunch of pieces of code accidentally thrown in by many different programmers from around the world, without any goal in mind, completely unguided. We were lucky that it somehow turned out useful. It’s called “emergent functionality”, in case you don’t know it. I see you don’t understand evolution. Go and take some basic biology 101. That should help you next time.
🙂
PS. my cheek hurts badly
gpuccio @204:
Ostrich policy!
That explains their conspicuous absence from these discussions!
Thanks!
gpuccio @203:
Yes, agree.
Dio at 201
Yep. Pattee was born in 1921 and graduated from Stanford in 1948. Barbieri was born in 1940 and graduated from Ferrara in 1964.
They ended up with the only conclusion that was professionally allowed to them. That’s the ideological damage done to science. Beyond saying they were “men of their times”, I do not know how to properly classify them. I know that I am personally grateful to both.
Upright BiPed:
“I know that I am personally grateful to both.”
And you are right to be grateful. Intelligent and creative argumentation is always precious, even if it takes place in a wrong context. 🙂
gpuccio @134:
“By the way, Figures 3,4, 5 and 6 (and their respective legends) are some more fun for the lovers of simplicity!”
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Yes, very simple indeed!
Dionisio, Gpuccio, Upright Biped,
re: Barbieri and Pattee
UB said,
So true in being grateful. Seeing Barbieri's Code Biology is refreshing even if he refuses to accept Design. At least he acknowledges signs and signals cannot exist without symbolic representation and meaning. Even if the tries to "naturalize" it.
Question, although we have places like UD and Discovery Institute today, are the times worse today for scientist?
As was seen in recent past and often we forget damage done in harsher treatment. For example, locking a scientist out of his office?
Richard Steinberg’s wretched treatment at Smithsonian
With those kind of treatments, discouraging open and free thought by scientist is it any wonder most would not “go there” to Design Theory?
Moving on…
Maybe, a modern day version of Babieri and Pattee is James Shapiro? of Third Way and “Natural” Genetic Engineering?
Since when is engineering a “natural” function without conscious thought? Without Design principles firmly glued to the functional thought process of mindful forethought of an Engineer?
Only when as in our times, it is not allowed without damaging repercussions to one’s job, livelihood and professional reputation.
Or, is Shapiro like Darwin? An end-run attempt around well known Design principles? Mainly around Code, Semantics, Semiosis and Engineering principles, but prefaced with “Natural” as an internal edification to his soul because he cannot accept it any other way?
I’ve not read any of his personal musings on it, but it seems even though we have the power of the Internet and brave people are fighting a good fight in these times. Still scientist are rarely allowed to speak openly without severe consequences and shaming. And most do not do so unless retired, or protected by tenure.
And who can blame them? Maybe as Dr. Sanford and others, many will quietly publish and “come out” when they can in the future.
Pattee and Barieri could not but help admit partially the truth before them.
This, even if they refuse the truth before them still helps our cause. The Thought Minders hate it.
Viva pensiero libero 🙂
.
DATCG @156:
Does that paper have DOI code?
DATCG @157,
Is that the same paper referenced @178-180 too?
@127: List of papers referenced in the OP
List of papers referenced by GP in comments posted in this thread:
1. Boisvert, François-Michel, Yasmeen Ahmad, Marek Gierli?ski, Fabien Charrière, Douglas Lamont, Michelle Scott, Geoff Barton, and Angus I. Lamond. “A Quantitative Spatial Proteomics Analysis of Proteome Turnover in Human Cells.” Molecular & Cellular Proteomics 11, no. 3 (March 2012): M111.011429. https://doi.org/10.1074/mcp.M111.011429.
2. Cao, Jian, and Qin Yan. “Histone Ubiquitination and Deubiquitination in Transcription, DNA Damage Response, and Cancer.” Frontiers in Oncology 2 (2012). https://doi.org/10.3389/fonc.2012.00026.
3. Cheng, Xiaoxiang, Jun Zheng, Gang Li, Verena Göbel, and Hongjie Zhang. “Degradation for Better Survival? Role of Ubiquitination in Epithelial Morphogenesis: Ubiquitination in Epithelial Morphogenesis.” Biological Reviews, March 1, 2018. https://doi.org/10.1111/brv.12404.
4. Choi, Jihye, and Kwang-Hyun Baek. “Cellular Functions of Stem Cell Factors Mediated by the Ubiquitin–proteasome System.” Cellular and Molecular Life Sciences, February 8, 2018. https://doi.org/10.1007/s00018-018-2770-7.
5. Citterio, Elisabetta. “Fine-Tuning the Ubiquitin Code at DNA Double-Strand Breaks: Deubiquitinating Enzymes at Work.” Frontiers in Genetics 6 (September 8, 2015). https://doi.org/10.3389/fgene.2015.00282.
6. Clague, Michael J., Claire Heride, and Sylvie Urbé. “The Demographics of the Ubiquitin System.” Trends in Cell Biology 25, no. 7 (July 2015): 417–26. https://doi.org/10.1016/j.tcb.2015.03.002.
7. Darwin, K. Heran. “Prokaryotic Ubiquitin-like Protein (Pup), Proteasomes and Pathogenesis.” Nature Reviews Microbiology 7, no. 7 (July 2009): 485–91. https://doi.org/10.1038/nrmicro2148.
8. Donovan, Prudence, and Philip Poronnik. “Nedd4 and Nedd4-2: Ubiquitin Ligases at Work in the Neuron.” The International Journal of Biochemistry & Cell Biology 45, no. 3 (March 2013): 706–10. https://doi.org/10.1016/j.biocel.2012.12.006.
9. Durston, Kirk K, David KY Chiu, David L Abel, and Jack T Trevors. “Measuring the Functional Sequence Complexity of Proteins.” Theoretical Biology and Medical Modelling 4, no. 1 (2007): 47. https://doi.org/10.1186/1742-4682-4-47.
10. Ebner, Petra, Gijs A. Versteeg, and Fumiyo Ikeda. “Ubiquitin Enzymes in the Regulation of Immune Responses.” Critical Reviews in Biochemistry and Molecular Biology 52, no. 4 (July 4, 2017): 425–60. https://doi.org/10.1080/10409238.2017.1325829.
11. Gao, Si-Fa, Bo Zhong, and Dandan Lin. “Regulation of T Helper Cell Differentiation by E3 Ubiquitin Ligases and Deubiquitinating Enzymes.” International Immunopharmacology 42 (January 2017): 150–56. https://doi.org/10.1016/j.intimp.2016.11.013.
12. George, Arlene J., Yarely C. Hoffiz, Antoinette J. Charles, Ying Zhu, and Angela M. Mabb. “A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders.” Frontiers in Genetics 9 (February 14, 2018). https://doi.org/10.3389/fgene.2018.00029.
13. Guharoy, Mainak, Pallab Bhowmick, and Peter Tompa. “Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System.” Journal of Biological Chemistry 291, no. 13 (March 25, 2016): 6723–31. https://doi.org/10.1074/jbc.R115.692665.
14. Gupta, Ishita, Kanika Singh, Nishant K. Varshney, and Sameena Khan. “Delineating Crosstalk Mechanisms of the Ubiquitin Proteasome System That Regulate Apoptosis.” Frontiers in Cell and Developmental Biology 6 (February 9, 2018). https://doi.org/10.3389/fcell.2018.00011.
15. Hallengren, Jada, Ping-Chung Chen, and Scott M. Wilson. “Neuronal Ubiquitin Homeostasis.” Cell Biochemistry and Biophysics 67, no. 1 (September 2013): 67–73. https://doi.org/10.1007/s12013-013-9634-4.
16. Hatakeyama, Shigetsugu. “TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis.” Trends in Biochemical Sciences 42, no. 4 (April 2017): 297–311. https://doi.org/10.1016/j.tibs.2017.01.002.
17. Hu, Ming-Ming, and Hong-Bing Shu. “Multifaceted Roles of TRIM38 in Innate Immune and Inflammatory Responses.” Cellular & Molecular Immunology 14, no. 4 (April 2017): 331–38. https://doi.org/10.1038/cmi.2016.66.
18. “Identification of Top-Ranked Proteins within a Directional Protein Interaction Network Using the PageRank Algorithm: Applications in Humans and Plants.” Current Issues in Molecular Biology, 2016. https://doi.org/10.21775/cimb.020.013.
19. Lee, Robin van der, Marija Buljan, Benjamin Lang, Robert J. Weatheritt, Gary W. Daughdrill, A. Keith Dunker, Monika Fuxreiter, et al. “Classification of Intrinsically Disordered Regions and Proteins.” Chemical Reviews 114, no. 13 (July 9, 2014): 6589–6631. https://doi.org/10.1021/cr400525m.
20. Li, Tao, Linsheng Wang, Yongming Du, Si Xie, Xi Yang, Fuming Lian, Zhongjun Zhou, and Chengmin Qian. “Structural and Mechanistic Insights into UHRF1-Mediated DNMT1 Activation in the Maintenance DNA Methylation.” Nucleic Acids Research, February 19, 2018. https://doi.org/10.1093/nar/gky104.
21. Liu, Jiangang, Narayanan B. Perumal, Christopher J. Oldfield, Eric W. Su, Vladimir N. Uversky, and A. Keith Dunker. “Intrinsic Disorder in Transcription Factors †.” Biochemistry 45, no. 22 (June 2006): 6873–88. https://doi.org/10.1021/bi0602718.
22. Maupin-Furlow, Julie A. “Prokaryotic Ubiquitin-Like Protein Modification.” Annual Review of Microbiology 68, no. 1 (September 8, 2014): 155–75. https://doi.org/10.1146/annurev-micro-091313-103447.
23. Ohtake, Fumiaki, Yasushi Saeki, Satoshi Ishido, Jun Kanno, and Keiji Tanaka. “The K48-K63 Branched Ubiquitin Chain Regulates NF-?B Signaling.” Molecular Cell 64, no. 2 (October 2016): 251–66. https://doi.org/10.1016/j.molcel.2016.09.014.
24. Ong, Taren, and David J. Solecki. “Seven in Absentia E3 Ubiquitin Ligases: Central Regulators of Neural Cell Fate and Neuronal Polarity.” Frontiers in Cellular Neuroscience 11 (October 13, 2017). https://doi.org/10.3389/fncel.2017.00322.
25. Park, Yoon, Hyung-seung Jin, Daisuke Aki, Jeeho Lee, and Yun-Cai Liu. “The Ubiquitin System in Immune Regulation.” In Advances in Immunology, 124:17–66. Elsevier, 2014. https://doi.org/10.1016/B978-0-12-800147-9.00002-9.
26. Saeki, Yasushi. “Ubiquitin Recognition by the Proteasome.” Journal of Biochemistry, January 8, 2017, mvw091. https://doi.org/10.1093/jb/mvw091.
27. Sammak, Susan, and Giovanna Zinzalla. “Targeting Protein–protein Interactions (PPIs) of Transcription Factors: Challenges of Intrinsically Disordered Proteins (IDPs) and Regions (IDRs).” Progress in Biophysics and Molecular Biology 119, no. 1 (October 2015): 41–46. https://doi.org/10.1016/j.pbiomolbio.2015.06.004.
28. Smeenk, Godelieve, and Niels Mailand. “Writers, Readers, and Erasers of Histone Ubiquitylation in DNA Double-Strand Break Repair.” Frontiers in Genetics 7 (June 28, 2016). https://doi.org/10.3389/fgene.2016.00122.
29. Su, Xiaomin, Chenglei Wu, Xiaoying Ye, Ming Zeng, Zhujun Zhang, Yongzhe Che, Yuan Zhang, Lin Liu, Yushuang Lin, and Rongcun Yang. “Embryonic Lethality in Mice Lacking Trim59 Due to Impaired Gastrulation Development.” Cell Death & Disease 9, no. 3 (March 2018). https://doi.org/10.1038/s41419-018-0370-y.
30. van der Lee, Robin, Benjamin Lang, Kai Kruse, Jörg Gsponer, Natalia Sánchez de Groot, Martijn A. Huynen, Andreas Matouschek, Monika Fuxreiter, and M. Madan Babu. “Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution.” Cell Reports 8, no. 6 (September 2014): 1832–44. https://doi.org/10.1016/j.celrep.2014.07.055.
31. Yamada, Tomoko, Yue Yang, and Azad Bonni. “Spatial Organization of Ubiquitin Ligase Pathways Orchestrates Neuronal Connectivity.” Trends in Neurosciences 36, no. 4 (April 2013): 218–26. https://doi.org/10.1016/j.tins.2012.12.004.
32. Yruela, Inmaculada, Christopher J. Oldfield, Karl J. Niklas, and A. Keith Dunker. “Evidence for a Strong Correlation Between Transcription Factor Protein Disorder and Organismic Complexity.” Genome Biology and Evolution 9, no. 5 (May 2017): 1248–65. https://doi.org/10.1093/gbe/evx073.
33. Yu, Houqing, and Andreas Matouschek. “Recognition of Client Proteins by the Proteasome.” Annual Review of Biophysics 46, no. 1 (May 22, 2017): 149–73. https://doi.org/10.1146/annurev-biophys-070816-033719.
34. Zhou, Bangjun, and Lirong Zeng. “Conventional and Unconventional Ubiquitination in Plant Immunity: Ubiquitination in Plant Immunity.” Molecular Plant Pathology 18, no. 9 (December 2017): 1313–30. https://doi.org/10.1111/mpp.12521.
Please, correct any inaccuracies or omissions in the above list. Thanks.
Please, note that the above list does not include papers referenced in the OP.
List of papers referenced by GP in comments posted in this thread:
George et al., “A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders”;
Boisvert et al., “A Quantitative Spatial Proteomics Analysis of Proteome Turnover in Human Cells”;
Choi and Baek, “Cellular Functions of Stem Cell Factors Mediated by the Ubiquitin–proteasome System”;
van der Lee et al., “Classification of Intrinsically Disordered Regions and Proteins”;
Zhou and Zeng, “Conventional and Unconventional Ubiquitination in Plant Immunity”;
Cheng et al., “Degradation for Better Survival?”;
Gupta et al., “Delineating Crosstalk Mechanisms of the Ubiquitin Proteasome System That Regulate Apoptosis”;
Guharoy, Bhowmick, and Tompa, “Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System”;
Su et al., “Embryonic Lethality in Mice Lacking Trim59 Due to Impaired Gastrulation Development”;
Yruela et al., “Evidence for a Strong Correlation Between Transcription Factor Protein Disorder and Organismic Complexity”;
Citterio, “Fine-Tuning the Ubiquitin Code at DNA Double-Strand Breaks”;
Cao and Yan, “Histone Ubiquitination and Deubiquitination in Transcription, DNA Damage Response, and Cancer”;
“Identification of Top-Ranked Proteins within a Directional Protein Interaction Network Using the PageRank Algorithm”;
Liu et al., “Intrinsic Disorder in Transcription Factors †”;
van der Lee et al., “Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution”;
Durston et al., “Measuring the Functional Sequence Complexity of Proteins”;
Hu and Shu, “Multifaceted Roles of TRIM38 in Innate Immune and Inflammatory Responses”;
Donovan and Poronnik, “Nedd4 and Nedd4-2”;
Hallengren, Chen, and Wilson, “Neuronal Ubiquitin Homeostasis”;
Darwin, “Prokaryotic Ubiquitin-like Protein (Pup), Proteasomes and Pathogenesis”;
Maupin-Furlow, “Prokaryotic Ubiquitin-Like Protein Modification”;
Yu and Matouschek, “Recognition of Client Proteins by the Proteasome”;
Gao, Zhong, and Lin, “Regulation of T Helper Cell Differentiation by E3 Ubiquitin Ligases and Deubiquitinating Enzymes”;
Ong and Solecki, “Seven in Absentia E3 Ubiquitin Ligases”;
Yamada, Yang, and Bonni, “Spatial Organization of Ubiquitin Ligase Pathways Orchestrates Neuronal Connectivity”;
Li et al., “Structural and Mechanistic Insights into UHRF1-Mediated DNMT1 Activation in the Maintenance DNA Methylation”;
Sammak and Zinzalla, “Targeting Protein–protein Interactions (PPIs) of Transcription Factors”;
Clague, Heride, and Urbé, “The Demographics of the Ubiquitin System”;
Ohtake et al., “The K48-K63 Branched Ubiquitin Chain Regulates NF-?B Signaling”;
Park et al., “The Ubiquitin System in Immune Regulation”;
Hatakeyama, “TRIM Family Proteins”; Ebner, Versteeg, and Ikeda, “Ubiquitin Enzymes in the Regulation of Immune Responses”;
Saeki, “Ubiquitin Recognition by the Proteasome”;
Smeenk and Mailand, “Writers, Readers, and Erasers of Histone Ubiquitylation in DNA Double-Strand Break Repair.”
Please, correct any inaccuracies or omissions in the above list. Thanks.
Please, note that the above list does not include papers referenced in the OP.
List of papers referenced by DATCG in comments posted in this thread:
1. Abel, David L., and Jack T. Trevors. “Three Subsets of Sequence Complexity and Their Relevance to Biopolymeric Information.” Theoretical Biology and Medical Modelling 2, no. 1 (August 11, 2005): 29. https://doi.org/10.1186/1742-4682-2-29.
2. Durston, Kirk K, David KY Chiu, Andrew KC Wong, and Gary CL Li. “Statistical Discovery of Site Inter-Dependencies in Sub-Molecular Hierarchical Protein Structuring.” EURASIP Journal on Bioinformatics and Systems Biology 2012, no. 1 (December 2012). https://doi.org/10.1186/1687-4153-2012-8.
3. Pla, A, M Pascual, J Renau-Piqueras, and C Guerri. “TLR4 Mediates the Impairment of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways Induced by Ethanol Treatment in Brain.” Cell Death & Disease 5, no. 2 (February 2014): e1066–e1066. https://doi.org/10.1038/cddis.2014.46.
4. Rogers, J. M., V. Oleinikovas, S. L. Shammas, C. T. Wong, D. De Sancho, C. M. Baker, and J. Clarke. “Interplay between Partner and Ligand Facilitates the Folding and Binding of an Intrinsically Disordered Protein.” Proceedings of the National Academy of Sciences 111, no. 43 (October 28, 2014): 15420–25. https://doi.org/10.1073/pnas.1409122111.
5. Ruiz i Altaba, Ariel, Vân Nguyên, and Verónica Palma. “The Emergent Design of the Neural Tube: Prepattern, SHH Morphogen and GLI Code.” Current Opinion in Genetics & Development 13, no. 5 (October 2003): 513–21. https://doi.org/10.1016/j.gde.2003.08.005.
6. Savage, Kienan I., and D. Paul Harkin. “BRCA1, a ‘Complex’ Protein Involved in the Maintenance of Genomic Stability.” The FEBS Journal 282, no. 4 (February 2015): 630–46. https://doi.org/10.1111/febs.13150.
7. Srikanthan, S., W. Li, R. L. Silverstein, and T. M. McIntyre. “Exosome Poly-Ubiquitin Inhibits Platelet Activation, Downregulates CD36 and Inhibits pro-Atherothombotic Cellular Functions.” Journal of Thrombosis and Haemostasis 12, no. 11 (November 2014): 1906–17. https://doi.org/10.1111/jth.12712.
8. Uversky, Vladimir N. “Functional Roles of Transiently and Intrinsically Disordered Regions within Proteins.” FEBS Journal 282, no. 7 (April 2015): 1182–89. https://doi.org/10.1111/febs.13202.
9. Wang, Yi-Ting, and Guang-Chao Chen. “The Role of Ubiquitin System in Autophagy.” In Autophagy in Current Trends in Cellular Physiology and Pathology, edited by Nikolai V. Gorbunov and Marion Schneider. InTech, 2016. https://doi.org/10.5772/64728.
Please, correct any inaccuracies or omissions in the above list. Thanks.
List of papers referenced by Dionisio in comments posted in this thread:
1. Adams, Katherine R., Sitara Chauhan, Divya B. Patel, Virginia K. Clements, Yan Wang, Steven M. Jay, Nathan J. Edwards, Suzanne Ostrand-Rosenberg, and Catherine Fenselau. “Ubiquitin Conjugation Probed by Inflammation in Myeloid-Derived Suppressor Cell Extracellular Vesicles.” Journal of Proteome Research 17, no. 1 (January 5, 2018): 315–24. https://doi.org/10.1021/acs.jproteome.7b00585.
2. Bremer, Anne, Martin Wolff, Anja Thalhammer, and Dirk K. Hincha. “Folding of Intrinsically Disordered Plant LEA Proteins Is Driven by Glycerol-Induced Crowding and the Presence of Membranes.” The FEBS Journal 284, no. 6 (March 2017): 919–36. https://doi.org/10.1111/febs.14023.
3. Burroughs, A. Maxwell, Lakshminarayan M. Iyer, and L. Aravind. “Structure and Evolution of Ubiquitin and Ubiquitin-Related Domains.” In Ubiquitin Family Modifiers and the Proteasome, edited by R. Jürgen Dohmen and Martin Scheffner, 832:15–63. Totowa, NJ: Humana Press, 2012. https://doi.org/10.1007/978-1-61779-474-2_2.
4. Chatzidaki-Livanis, Maria, Michael J. Coyne, Kevin G. Roelofs, Rahul R. Gentyala, Jarreth M. Caldwell, and Laurie E. Comstock. “Gut Symbiont Bacteroides Fragilis Secretes a Eukaryotic-Like Ubiquitin Protein That Mediates Intraspecies Antagonism.” Edited by John J. Mekalanos. MBio 8, no. 6 (November 28, 2017): e01902-17. https://doi.org/10.1128/mBio.01902-17.
5. Choudhury, Nila Roy, Gregory Heikel, Maryia Trubitsyna, Peter Kubik, Jakub Stanislaw Nowak, Shaun Webb, Sander Granneman, et al. “RNA-Binding Activity of TRIM25 Is Mediated by Its PRY/SPRY Domain and Is Required for Ubiquitination.” BMC Biology 15, no. 1 (December 2017). https://doi.org/10.1186/s12915-017-0444-9.
6. Dubrez, Laurence. “Regulation of E2F1 Transcription Factor by Ubiquitin Conjugation.” International Journal of Molecular Sciences 18, no. 12 (October 19, 2017): 2188. https://doi.org/10.3390/ijms18102188.
7. Gadhave, Kundlik, Nityanand Bolshette, Ashutosh Ahire, Rohit Pardeshi, Krishan Thakur, Cristiana Trandafir, Alexandru Istrate, et al. “The Ubiquitin Proteasomal System: A Potential Target for the Management of Alzheimer’s Disease.” Journal of Cellular and Molecular Medicine 20, no. 7 (July 2016): 1392–1407. https://doi.org/10.1111/jcmm.12817.
8. Gilberto, Samuel, and Matthias Peter. “Dynamic Ubiquitin Signaling in Cell Cycle Regulation.” The Journal of Cell Biology 216, no. 8 (August 7, 2017): 2259–71. https://doi.org/10.1083/jcb.201703170.
9. Gupta, Nilaksh, Wei Li, and Thomas M. McIntyre. “Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and ThrombosisSignificance.” Arteriosclerosis, Thrombosis, and Vascular Biology 35, no. 12 (December 2015): 2657–66. https://doi.org/10.1161/ATVBAHA.115.306054.
10. Hentze, Matthias W., Alfredo Castello, Thomas Schwarzl, and Thomas Preiss. “A Brave New World of RNA-Binding Proteins.” Nature Reviews Molecular Cell Biology, January 17, 2018. https://doi.org/10.1038/nrm.2017.130.
11. Huang, Anqi, Christopher Amourda, Shaobo Zhang, Nicholas S Tolwinski, and Timothy E Saunders. “Decoding Temporal Interpretation of the Morphogen Bicoid in the Early Drosophila Embryo.” ELife 6 (July 10, 2017). https://doi.org/10.7554/eLife.26258.
12. Krupina, Ksenia, Charlotte Kleiss, Thibaud Metzger, Sadek Fournane, Stephane Schmucker, Kay Hofmann, Benoit Fischer, et al. “Ubiquitin Receptor Protein UBASH3B Drives Aurora B Recruitment to Mitotic Microtubules.” Developmental Cell 36, no. 1 (January 2016): 63–78. https://doi.org/10.1016/j.devcel.2015.12.017.
13. Lee, Sora, Jessica M Tumolo, Aaron C Ehlinger, Kristin K Jernigan, Susan J Qualls-Histed, Pi-Chiang Hsu, W Hayes McDonald, Walter J Chazin, and Jason A MacGurn. “Ubiquitin Turnover and Endocytic Trafficking in Yeast Are Regulated by Ser57 Phosphorylation of Ubiquitin.” ELife 6 (November 13, 2017). https://doi.org/10.7554/eLife.29176.
14. Lin, Pei-Hui, Matthew Sermersheim, Haichang Li, Peter Lee, Steven Steinberg, and Jianjie Ma. “Zinc in Wound Healing Modulation.” Nutrients 10, no. 2 (December 24, 2017): 16. https://doi.org/10.3390/nu10010016.
15. Martinez, Aitor, Benoit Lectez, Juanma Ramirez, Oliver Popp, James D. Sutherland, Sylvie Urbé, Gunnar Dittmar, Michael J. Clague, and Ugo Mayor. “Quantitative Proteomic Analysis of Parkin Substrates in Drosophila Neurons.” Molecular Neurodegeneration 12, no. 1 (December 2017). https://doi.org/10.1186/s13024-017-0170-3.
16. Matsuo, Naoki, Natsuko Goda, Kana Shimizu, Satoshi Fukuchi, Motonori Ota, and Hidekazu Hiroaki. “Discovery of Cryoprotective Activity in Human Genome-Derived Intrinsically Disordered Proteins.” International Journal of Molecular Sciences 19, no. 2 (January 30, 2018): 401. https://doi.org/10.3390/ijms19020401.
17. Mukherjee, Rukmini, Aneesha Das, Saikat Chakrabarti, and Oishee Chakrabarti. “Calcium Dependent Regulation of Protein Ubiquitination – Interplay between E3 Ligases and Calcium Binding Proteins.” Biochimica et Biophysica Acta (BBA) – Molecular Cell Research 1864, no. 7 (July 2017): 1227–35. https://doi.org/10.1016/j.bbamcr.2017.03.001.
18. Penke, Botond, Ferenc Bogár, Tim Crul, Miklós Sántha, Melinda Tóth, and László Vígh. “Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions.” International Journal of Molecular Sciences 19, no. 2 (January 22, 2018): 325. https://doi.org/10.3390/ijms19010325.
19. Pinto, Maria J., Joana R. Pedro, Rui O. Costa, and Ramiro D. Almeida. “Visualizing K48 Ubiquitination during Presynaptic Formation By Ubiquitination-Induced Fluorescence Complementation (UiFC).” Frontiers in Molecular Neuroscience 9 (June 10, 2016). https://doi.org/10.3389/fnmol.2016.00043.
20. Seissler, Tanja, Roland Marquet, and Jean-Christophe Paillart. “Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins.” Viruses 9, no. 12 (October 31, 2017): 322. https://doi.org/10.3390/v9110322.
21. Sigalov, Alexander B. “Structural Biology of Intrinsically Disordered Proteins: Revisiting Unsolved Mysteries.” Biochimie 125 (June 2016): 112–18. https://doi.org/10.1016/j.biochi.2016.03.006.
22. Sparrer, Konstantin M. J., and Michaela U. Gack. “TRIM Proteins: New Players in Virus-Induced Autophagy.” Edited by Rebecca Ellis Dutch. PLOS Pathogens 14, no. 2 (February 1, 2018): e1006787. https://doi.org/10.1371/journal.ppat.1006787.
23. Tol, Sarah van, Adam Hage, Maria Giraldo, Preeti Bharaj, and Ricardo Rajsbaum. “The TRIMendous Role of TRIMs in Virus–Host Interactions.” Vaccines 5, no. 4 (August 22, 2017): 23. https://doi.org/10.3390/vaccines5030023.
24. Uversky, Vladimir N. “The Multifaceted Roles of Intrinsic Disorder in Protein Complexes.” FEBS Letters 589, no. 19PartA (September 14, 2015): 2498–2506. https://doi.org/10.1016/j.febslet.2015.06.004.
25. Yan, Kaowen, Li Li, Xiaojian Wang, Ruisha Hong, Ying Zhang, Hua Yang, Ming Lin, et al. “The Deubiquitinating Enzyme Complex BRISC Is Required for Proper Mitotic Spindle Assembly in Mammalian Cells.” The Journal of Cell Biology 210, no. 2 (July 20, 2015): 209–24. https://doi.org/10.1083/jcb.201503039.
Please, correct any inaccuracies or omissions in the above list. Thanks.
Dio,
Here’s the DOI for #156
DOI: 10.1186/1687-4153-2012-8 · Source: PubMed
re: 157, yes,
Comments 178-180 reference the Figures which I found
fascinating of Durston, Wong, et al., in using their K-mode
algorithm and how they represented it graphically.
Digging a bit deeper into pre-ubiqutionation, E1 phase. Trying to understand signals that kick-off Ubiquitin tagging.
Interesting paper from 2009, on Signaling Degradation,
Degrons N-End Pathway, and Ubiquitin
Was curious how, where, when Ubiquitin was called upon(“signaled”), to respond. Either for Damaged Proteins or normal Rates of Turnover for Proteins.
So, from the beginning to the end, paper and quotes…
Degradation Signal Diversity in the Ubiquitin-Proteasome System
Open Access
Nat Rev Mol Cell Biol. Author manuscript; available in PMC 2009 Mar 1.
Published in final edited form as:
Nat Rev Mol Cell Biol. 2008 Sep; 9(9): 679–690.
doi: 10.1038/nrm2468
Introduction
Intracellular protein degradation has been studied for more than half a century, and it became clear early on that such degradation is highly selective, with individual protein half-lives ranging from minutes to years (for reviews of the early literature, see refs. 1-2). Moreover, much of this degradation was found to be energy-dependent despite the exergonic nature of peptide-bond cleavage. This energy dependence derives from the dual requirements of high substrate specificity and substrate protein unfolding to make the polypeptide backbone fully accessible for proteolytic cleavage.
The vast majority of regulated protein degradation in eukaryotes is executed by the ubiquitin-proteasome system 3-5. Polyubiquitin tagging of substrates by specific enzymes provides the major source of selectivity in the system (Box 1), whereas the 26S proteasome complex performs the protein unfolding necessary for processive cleavage of the tagged proteins into short peptides (Box 2).
In addition, ubiquitin ligation can function independently of the proteasome by directing certain -usually membrane- proteins to the lysosome/vacuole for proteolysis. Conversely, proteasomes can degrade some proteins without their prior modification by ubiquitin.
“Signals” and Targeting
“Design of different Degrons”
N-degrons and the N-end rule pathway
Degrons in the ER
Concluding remarks
.
.
In summary, what came first, the Signal, the Recognizer, the Tagger, the Receiver, the Cleaver, the Recycler?
And since when does a blind system know what to recycle? And what NOT to recycle?
.
Degron Wiki Reference…
A Degron is…
Two-step, Three-step Identification
Note on Degrons.
Gpuccio posted papers in Original Post, noting use of Degrons, one behind a paywall.
And another at Comment #10 interestingly enough titled…
“Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System”
🙂
Part of the text Gpuccio highlighted…
Disordered as we remember being Flexible, Conditional and Context dependent.
.
Upright Biped, Dionisio, Gpuccio,
Martello Barbieri’s inspired Biosemetics Journal has this
in it’s first paragraph…
“… attempt to naturalize biological meaning”
is an interesting way to put it and a “challenge” indeed.
DATCG,
Apparently not all the complex biological processes dealing with functionally specified information can be easily described through biosemiotics principles. For example, as we discussed earlier in this thread [ @54 & @69 ], spatiotemporal signal concentration profiles (a.k.a. morphogen gradients) are not easily associated with biosemiotics or codes, because -unlike translation- the effectors seem embedded in the process without discontinuity.
DATCG @219:
Thanks for the information.
DATCG,
Regarding the comment @224, see also @74-77.
That particular issue was briefly discussed @54, @69, and @74 through 77.
DATCG at #220:
Very interesting paper about degrons.
Indeed, this is of course the set of “signals” that the E3-E2 complex must be able to recognize. That adds to the semiosis of the system.
So, the E3 ligase(complexed to its E2) must be able to:
a) Recognize its specific protein substrate.
b) Recognize some specific degron signal in that substarte (at least for protein degradation which, as we know, is not the only target od ubiquitination).
c) Be able to apply the correct ubiquitination signal to that specific target with that specific degron signal.
This extreme semiotic complexity is very interesting, and of course must have very good motivations. In theory, we could think of some much simpler system, which can recognize a few degron signal on any protein, and aplly some standard degradation signal to them all.
But that’s not the case. In the ubiquitin system, each combinatorial formula of degron signal and ubiquitin signal is applied in a specific way to a specific substrate.
That’s why we have all those E2, and especially E3, complex molecule.
Substrate recognition is the key to all, and it strictly conditions degron signal recognition and ubiquitin signal application.
Again, the engineering resources linked to tis system are amazing, and of course the real purpose of all this must be to make an extremely fine-tuned regulation of cellular processes possible.
DATCG, Upright Biped, Dionisio:
It’s also interesting to remark that protein degradation (which, again, is not the only task of ubiquitination) has at least wto completely different purposes:
a) Degrading proteins which are not really functional, or are not really functional any more (so calle Protein Quality control). If I understand well, this is mainly accomplished by lysosome autophagy, especially for damaged big structures, like mitochondria.
b) Controlling the concentration of key regulatory or effector proteins, whose levels must be stable but readily adjustable according to conditions. This is of course a much finer task, accomplished by intervening on highly dynamic physical systems.
The two things are completely different in concept and, of course, implementation, and it’s really surprising that the same ubiquitin system presides to both! 🙂
DATCG,
Please help me with this:
@219 you wrote:
Referring to your comment @156, where you wrote:
The link you provided @156 points to this:
https://www.researchgate.net/publication/275892308_Functional_Sequence_Complexity_FSC_measured_in_fits
Which includes the full text PDF of the given paper.
However, the DOI you just provided @219 points to this:
https://bsb-eurasipjournals.springeropen.com/articles/10.1186/1687-4153-2012-8
Am I missing something?
Thanks
“Evolution of the Ubiquitin system? … ”
The problem of evolution of anything always boils down to the distinction between specificity and non-specificity. That is why the problem of evolution is generic and we don’t need to name or identify any particular biological component, system or function, but only two things:
A) the number of particles comprising biological components
B) the level of specificity that retains a functional role of a component in a system.
Here is detailed explanation:
https://biospecificity.wordpress.com/
gpuccio @228:
Does the above item ‘b’ relate to the issues addressed @226?
forexhr @230:
That’s an interesting contribution to the discussion. Thanks.
#229 Dio,
my mistake, looked again, there is no DOI for that paper by Abel. Might be it’s only published on his Emergence Project site.
#228 Gpuccio,
Precisely, “extremely fine-tuned” in the 2nd mode for Ubiquitin. It’s quite precarious process and explains why so many diseases crop up if not in sync.
On item a) degradation, I read a little bit about one scenario farther up processing ladder if aggregation forms. In eyes causing cataracts if not corrected.
But then there’s this news reported in 2015 on communications issues with Calpain from Tufts.
Mechanism involved in causing cataracts in mice identified by researchers
from Sciencedaily; Science News 2015
Summary
Cataracts is one of the Most Common Eye Diseases
Gpuccio,
re: your points…
“That’s why we have all those E2, and especially E3, complex molecule.”
It escalates for E3 as a need for Conditional Processing too? As well as specificity and context of the proteins.
Is that overstating it?
“Substrate recognition is the key to all, and it strictly conditions degron signal recognition and ubiquitin signal application.”
And if there are any changes, disease. My question would be what are threshold levels for limiting mutations to these working areas. And if this is well understood yet. We know abnormal proteins accumulate if a, b, c or d happen. But what are Fault-Tolerance levels.
“Again, the engineering resources linked to tis system are amazing, and of course the real purpose of all this must be to make an extremely fine-tuned regulation of cellular processes possible.”
Fine-tuned with error correction from step 1 to 1001 😉
Protein Quality Control Systems appear by blind process?
It is an amazing labyrinth of pathways, locks, keys, signals, cleavings, stackings and communications networks zooming around in the cells.
forexhr:
I think we probably agree on the main ideas.
Of course, I have some definite approaches to measuring functional information (specificity), and I rely a lot on sequence conservation throughout long evolutionary times.
DATCG at #234:
Calpain seems another additional calcium-regulated network for protein degradation. How many of them are there? 🙂
From Uniprot:
“Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Proteolytically cleaves MYOC at ‘Arg-226’ (PubMed:17650508). Proteolytically cleaves CPEB3 following neuronal stimulation which abolishes CPEB3 translational repressor activity, leading to translation of CPEB3 target mRNAs (By similarity).”
@237 Gpuccio,
How many and Why? 🙂
If it’s not due to random mutations and natural selection. If RM&NS there is no rhyme or reason.
But there must be practical reasons if by Design.
Calpain assist ubiquitin. Without it ubiquitination will not occur.
Non-lysosomal, hmmmm. We know the Proteosome cannot handle all proteins for degradation.
Tissue Specificity maybe or limits and controls, but there are others as you pointed out as well.
So we have multiple interfaces for specific task in and outside of the Ubiquitin framework that also coordinate with it for degradation and other task.
Each in it’s own realm of duties, rules and constraints.
DATCG @233,
OK, no problem.
Thanks.
#237 Gpuccio, Dionisio,
Another regulated network in coordination with mono and poly-Ubiquitin System. p97 or VCP.
Don’t think it was covered yet. Like you said Gpuccio, there must be many more. But I found this interesting as they’re using it to inhibit the Proteasome, RP11 and slow down cancerous tumors.
After watching Dr. Deshaies Video 2 & 3 again, I became curious of his commercial work.
Turns out he’s a Scientific Founder at Cleave Biosciences
working with different aspects of ubiquitin pathways and coordinated systems like VCP-p97.
They have research ongoing into P97 – a celluar AAA ATPase, with a “described role as master regulator in the (UPS) Ubiquitin Proteasome System.”
Here…
Cleave BioSciences Pipeline – P97
They have a very short Summary…
.
Continuing below…
Delete #241 please.
Continued…
Searched for more on VCP-p97 as regulator in Ubiqutin process.
Found this paper…
The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis
2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 1–7 doi:10.1242/jcs.093831
Hemmo Meyer1, and Conrad C. Weihl2
p97 functions also as interaction hub
Deubiquitylating Enzymes
p92 VCP ensures homeostasis in facilitating
proteasomal degradation of damaged or misfolded proteins
VCP-p97 non-degradative process of TFs
DNA double-stranded breaks
continued…
Figure 1 for above comment Includes VCP-p97 diagram functions and interactions with ubiquitin system.
Unfortunately not an SVG format. Does not scale well.
VCP-p97 – Ubiqiutin Systems and other Functions
DATCG:
You have definitely found a very important actor in the scene we have been debating! 🙂
VCP-p97 seems to be as elusive as its many names (TERA, Transitional endoplasmic reticulum ATPase, VCP, Valosin-containing protein, CDC48, and so on).
The same name of its protein family is astounding:
AAA+: extended family of ATPases associated with various cellular activities.
And various it is!
From Uniprot:
By the way, it is an 806 AAs long protein (in humans), extremely conserved in all eukaryotes (almost as much as ubiquitin).
78% identities and 89% positives in fungi, 1313 bits, 1.63 baa.
Complex structure, complex interactions, and definitely a prima donna in the ubiquitin drama.
The amazing thing is that, as usual, so many things are known about it (I am just starting to dig), and yet so little is really understood.
Maybe just a look at Wikipedia for a brief summary:
Now, I would say that what is called here the “general function”:
“The general function of p97/CDC48 is to segregate proteins from large protein assembly or immobile cellular structures such as membranes or chromatin, allowing the released protein molecules to be degraded by the proteasome.”
is as intriguing and undetailed as it can be!
However, the “structure” part (always in Wikipedia) is even better:
Emphasis mine.
Gpuccio,
Thanks for your detailed response, specifically on conservation in eukaryotes and humans, including the Blast stats!
On the conformational changes, it’s quite amazing what it goes through and this is yet again conditional.
Conserved together as they would have to be from the beginning for any of this to make sense, correct?
There is no(or very little) room for mutations here. Disease is the result if mutations impact these different systems working together on crucial time-dependent delivery.
Thus all the Quality Control systems and constraints in place to clear out mutations and damaged goods.
Hey guys, Dionisio, Gpuccio, UB, etc.,
What more is there to add? Anything we’re missing or have not covered? Or to highlight?
I’m tempted to post more papers but did not want to do so Gpuccio if you think the subject matter for this post has been fully expanded upon.
I think for me, there’s the overall picture, big image of the systems control aspects, semiosis, then Conserved Functions over time in eukaryotes you’ve highlighted.
These systems are so large, complex, integrated it’s hard to set back and look upon them as well understood units in a larger frame of reference.
Even with all the infographics, step by step processes, and videos, still hard to comprehend it all in formalized actions and conditions.
There’s one issue I do not understand in video 3 by Dr. Deshaies presentation on inhibiting cancerous tumors by blocking the Proteasome.
Looking at his commercial site, including some prescriptions approved we can see even targeted solutions still result in possible serious repercussions to people as side affects.
It seems the methods utilized today, though much better are a bit like using a hammer on a screw.
I thought from a Design perspective, it would be more upstream in detection systems or cutting off supply to the tumor by a better method. Or, farther upstream, detecting mutations that allow tumors to form in the first place and replacing those mutations – maybe – not saying it’s easy. Just thinking through the process. That would mean fully understanding the detailed circumstances that allowed the mutation upstream.
If it could be done, eliminating need for post-treatment of tumors after they’ve started. Which is late in the process. Though I would not rule out better Post-treatment methodology.
Just some thoughts.
@217 updated list (added 3 references posted after #217):
1. Abel, David L., and Jack T. Trevors. “Three Subsets of Sequence Complexity and Their Relevance to Biopolymeric Information.” Theoretical Biology and Medical Modelling 2, no. 1 (August 11, 2005): 29. https://doi.org/10.1186/1742-4682-2-29.
2. Durston, Kirk K, David KY Chiu, Andrew KC Wong, and Gary CL Li. “Statistical Discovery of Site Inter-Dependencies in Sub-Molecular Hierarchical Protein Structuring.” EURASIP Journal on Bioinformatics and Systems Biology 2012, no. 1 (December 2012). https://doi.org/10.1186/1687-4153-2012-8.
3. Liu, Ke, Lei Lyu, David Chin, Junyuan Gao, Xiurong Sun, Fu Shang, Andrea Caceres, et al. “Altered Ubiquitin Causes Perturbed Calcium Homeostasis, Hyperactivation of Calpain, Dysregulated Differentiation, and Cataract.” Proceedings of the National Academy of Sciences 112, no. 4 (January 27, 2015): 1071–76. https://doi.org/10.1073/pnas.1404059112.
4. Meyer, H., and C. C. Weihl. “The VCP/P97 System at a Glance: Connecting Cellular Function to Disease Pathogenesis.” Journal of Cell Science 127, no. 18 (September 15, 2014): 3877–83. https://doi.org/10.1242/jcs.093831.
5. Pla, A, M Pascual, J Renau-Piqueras, and C Guerri. “TLR4 Mediates the Impairment of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways Induced by Ethanol Treatment in Brain.” Cell Death & Disease 5, no. 2 (February 2014): e1066–e1066. https://doi.org/10.1038/cddis.2014.46.
6. Ravid, Tommer, and Mark Hochstrasser. “Diversity of Degradation Signals in the Ubiquitin–proteasome System.” Nature Reviews Molecular Cell Biology 9, no. 9 (September 2008): 679–89. https://doi.org/10.1038/nrm2468.
7. Rogers, J. M., V. Oleinikovas, S. L. Shammas, C. T. Wong, D. De Sancho, C. M. Baker, and J. Clarke. “Interplay between Partner and Ligand Facilitates the Folding and Binding of an Intrinsically Disordered Protein.” Proceedings of the National Academy of Sciences 111, no. 43 (October 28, 2014): 15420–25. https://doi.org/10.1073/pnas.1409122111.
8. Ruiz i Altaba, Ariel, Vân Nguyên, and Verónica Palma. “The Emergent Design of the Neural Tube: Prepattern, SHH Morphogen and GLI Code.” Current Opinion in Genetics & Development 13, no. 5 (October 2003): 513–21. https://doi.org/10.1016/j.gde.2003.08.005.
9. Savage, Kienan I., and D. Paul Harkin. “BRCA1, a ‘Complex’ Protein Involved in the Maintenance of Genomic Stability.” The FEBS Journal 282, no. 4 (February 2015): 630–46. https://doi.org/10.1111/febs.13150.
10. Srikanthan, S., W. Li, R. L. Silverstein, and T. M. McIntyre. “Exosome Poly-Ubiquitin Inhibits Platelet Activation, Downregulates CD36 and Inhibits pro-Atherothombotic Cellular Functions.” Journal of Thrombosis and Haemostasis 12, no. 11 (November 2014): 1906–17. https://doi.org/10.1111/jth.12712.
11. Uversky, Vladimir N. “Functional Roles of Transiently and Intrinsically Disordered Regions within Proteins.” FEBS Journal 282, no. 7 (April 2015): 1182–89. https://doi.org/10.1111/febs.13202.
12. Wang, Yi-Ting, and Guang-Chao Chen. “The Role of Ubiquitin System in Autophagy.” In Autophagy in Current Trends in Cellular Physiology and Pathology, edited by Nikolai V. Gorbunov and Marion Schneider. InTech, 2016. https://doi.org/10.5772/64728.
DATCG:
Well, I think we have certainly covered a lot of important and interesting issues. I certainly agree with your thoughts.
Please, feel free to post something new if you think it is worthwhile, or not to post if you prefer so. I will do more or less the same.
I think this whole subject is really good evidence for design, for a lot of different and intertwining reasons that we have tried to highlight in our “private party” here.
But our kind interlocutors probably think that all this is trivial or irrelevant, otherwise they would certainly have joined the discussion to show us out serious errors! 🙂
DATCG:
The problem of a functional, or “pathogenetic” therapy of tumours is complex, and in general rather frustrating.
For a lot of time the therapy of tumors and leukemias has been highly empirical, and based essentially on drugs which are toxic to all cells.
Understanding the biological features of neoplastic cells has always been a great aim, but unfortunately our increase in understanding has not always provided really useful therapeutic strategies.
However, things are probably changing, and maybe with time we can get better results.
About going upstream: I don’t know, “detecting mutations that allow tumors to form in the first place and replacing those mutations” seems still rather far away. Of course detecting tumors when they are still at the beginning would be great, but the problem is that they are really a lot of different things, from a biological point of view, even when they have similar clinical manifestations. And a lot of random events are probably implied in the initial phases of the disease. Here again complexity makes it difficult for us to really understand, and unfortunately it is here the complexity of possible random devastations of extremely complex functions.
But understanding is always the foundation for all. After understanding, some power of intervention must come, sooner or later.
Dionisio:
Thank you for your updates! 🙂
DATCG:
Again about VCP/p97/CDC48 (February 2017):
A Cdc48 “Retrochaperone” Function Is Required for the Solubility of Retrotranslocated, Integral Membrane Endoplasmic Reticulum-associated Degradation (ERAD-M) Substrates
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336148/
Retrochaperone?
So, a new function for our protein, as though the “old” functions were not enough!
Retrochaperone. 🙂
And, again, a critical role of ubiquitin chains.
DATCG @246:
gpuccio has covered (along with your contributions) a substantial area of important subtopics within the main theme of this thread. But note that the number of biology-related research papers seem to increase quite rapidly revealing interesting things that had not been considered until now. I would refrain from thinking the discussion has been exhausted.
As we saw, many details remain elusive at best.
As outstanding questions get answered, new ones are raised. This gives the impression of a never-ending story. The complexity of the functionally specified informational organization keeps deepening with no end in sight yet.
Gpuccio @248,
Well OK then, more to follow 🙂 Just wanted to make sure I was staying in the right theme of things.
Sounds great! And agree the neo-darwinist would certainly show up if they had a rebuttal.
#249 Gpuccio,
Yep agree with all you said. I think as I get an opportunity to peek inside how it’s done which is quite remarkable the explanation by Dr. Deshaies actually to do that it was very eye opening and at same time humbling at how far we have to go.
I humbly have no idea where to start, just a vague understanding at all. I’m guessing openly here, much out of ignorance that if we’re looking at a designed system, then we may find a pattern of weak-links(?) so to speak? That may eventually be understood as hot spots for deleterious mutations.
Ohhh yes… agree at the difficulty. Maybe I’m reaching to far when I say upstream, but for some reason think it’s not out of the realm of possibility to discover in the future.
Maybe a bit naive too. But I keep thinking if designed, then based upon environmental input – see how the branching of deleterious mutations form patterns of failure. That end in tumors. Then tracing it back upstream to the regulatory functions or master regulators even and other coordinated interdependencies.
It’s a mouthful of networking semantic diagnosis and reverse engineering! 🙂
#251 Gpuccio,
Congrats on finding a rarely used term, RetroChaperone! 🙂
Haha, I checked and wiki still does not have it. Only used mainly in this paper and a few others. Maybe chaperone is good enough, but retro sounds cool to identify along with retrotranslocation to the cytosol. They do speak about regulation of retro-translocation of chaperones but interestly not updated with Cdc48 yet! Wiki is falling behind 😉
And wow… yeah Cdc48 chaperoning misfolded ER local proteins to the cytosol. Maintaining solubility by binding to ubiquitinated ERAD M-substrates – retrotranslocated.
What can possibly go wrong? 😉
To degrade or not to degrade, this is the question of the protein life cycle.
I’ll review this new informatoin you provided. And I have other papers I put on hold as I’m working thru them.
Oh, during review of other papers, maybe my use of “upstream” is inappropriate? I’ve an old habit of thinking in terms of Top-down structured programming.
I’ll search for an example.
a bit of humor to add to the mix from some college students I’m guessing.
The sad case of a misfolded protein and UPR(Unfolded Protein Response) on the “Ugly Protein Network”
https://www.youtube.com/watch?v=XYGlzNnHoTw
#252, 253,
Agreed 🙂 And thanks for interesting abstract on chromosome segregation in mitosis and MCC Mitotitic Checkpoint Complex. And role of Ubiquitylation.
This comment is off-topic a bit. My pet peeve of Nomenclature and chaotic naming conventions of functions.
While searching on Choromsome Segregation and ubiquitination of open access papers I came across a Chapter by Mitsuhiro Yanagida.
Besides the main chapter, on basics of Chromosome Segregation which mentions ubiquitin interplay and roles
Yanagida mentions Nomenclature.
He points out the problem of Nomenclature at Chapter 2.4, pg 25. You may not be interested in this at all, but it’s 2nd person I’ve found frustrated a bit, detailing why it’s important for easy identification of functions. Another reason I personally think this is important is from a Design perspective.
The chapter automatically opens a PDF btw for download from Springer.com…
Basics of Chromosome Segregation – Mitsuhiro Yanagida – 2009
I like the points he is making about recognize Functions across organisms!
Thank you as a newcomer! 🙂 But hmmm, just as a systems molecular biologist it sure seems cumbersome, chaotic and unproductive as well.
Thank you Mitsuhiro Yanagida! He deserves an award for common sense 🙂 Not much about Ubiquitin but thank you for elucidating the problems of naming conventions across disparate areas.
@215 update the list – add the following item from gpuccio @251::
Neal, Sonya, Raymond Mak, Eric J. Bennett, and Randolph Hampton. “A Cdc48 ‘Retrochaperone’ Function Is Required for the Solubility of Retrotranslocated, Integral Membrane Endoplasmic Reticulum-Associated Degradation (ERAD-M) Substrates.” Journal of Biological Chemistry 292, no. 8 (February 24, 2017): 3112–28. https://doi.org/10.1074/jbc.M116.770610.
Dionisio, Gpuccio,
Question, do either of you have sources for images of Proteins that you like to refer to? Or for any active process and genetic material? If so, please share. Would like to build up different resources for viewing.
Came across a resource trying to find images of Ubiquitin Proteins. This is of WWP1(WW domain containing E3 ubiquitin protein ligase 1) This includes a HECT domain.
Atlas of Genetics and Cytogenetics in Oncology and Haematology – WWP1 containing E3 ubiquitin ligase 1 – Alias AIP5
The images of above link are of WWP1 expression in 22Rv1 prostate cancer cell line.
Descriptions, notations and info…
Morning Dio 🙂 Have a good day. I’m out for now.
DATCG @246:
gpuccio @251:
DATCG @259,
That’s interesting.
DATCG @261,
That’s interesting.
DATCG @262,
Thanks.
Dionisio @253:
You too are not bad at picking pèapers which “just came out of the printing press”! 🙂
I specially liked this phrase:
“When the checkpoint is satisfied, anaphase is initiated by the disassembly of MCC.”
(Emphasis mine)
After all, design is the tool to satisfy a desire. Maybe ubiqutin chians have a role in expressing satisfaction, too! 🙂
DATCG:
“And agree the neo-darwinist would certainly show up if they had a rebuttal.”
Maybe they are simply shy! 🙂
DATCG at #255:
“It’s a mouthful of networking semantic diagnosis and reverse engineering!”
Yes, but unfortunately sometimes it’s easier to buid something again than to repair it.
The problem with neoplastic cells is that, once the initial transformation takes place, a lot of further mutations or functional impairments is very likely to follow.
That’s also the reason for resistance to therapy in relapsed neploasias.
DATCG at #256:
It’s great to be ahead of Wikipedia! 🙂 🙂
gpuccio @265:
[emphasis added]
That reminds me of some loud musicians that couldn’t get no satisfaction, even though they kept trying (or at least that’s what they claimed) since the mid 1960s. 🙂
Maybe they didn’t know much about ubiquitin back then? 🙂
DATCG @254:
“And agree the neo-darwinist would certainly show up if they had a rebuttal.”
gpuccio @266:
“Maybe they are simply shy!”
No, they aren’t shy at all! 🙂
The most probable reason behind their conspicuous absence here is that most of what is discussed can be easily explained through RV+NS, hence this discussion is trivial and not worth their time. 🙂
Off topic.
Check this out at your convenience.
If you don’t want to watch the whole video, just skip to around the mark 30:00 and listen to the last ten minutes.
The visual part of the presentation is not very clear, which seems like a defect of the way the presentation was recorded. Maybe there is a better video of the same lecture?
https://www.youtube.com/embed/XbS2dwn04fQ
https://www.aices.rwth-aachen.de/en/
@271 addendum
isn’t professor Denis Noble one of the pioneers of systems biology and founder of the 3rd way (the raft some evolutionists are using to jump out of the sinking neo-Darwinian ship)?
The Ubiquitin Ligase (E3) Psh1p Is Required for Proper Segregation of both Centromeric and Two-Micron Plasmids in Saccharomyces cerevisiae
Meredith B. Metzger, Jessica L. Scales, Mitchell F. Dunklebarger and Allan M. Weissman
G3: Genes, Genomes, Genetics November 1, 2017 vol. 7 no. 11 3731-3743; https://doi.org/10.1534/g3.117.300227
http://www.g3journal.org/conte.....1.full.pdf
Dionisio at #273:
Interesting.
This strange E3 ligase, Psh1p, 406 AAs long, is practically taxonomycally restricted to Saccharomycetes. This is really amazing.
Indeed, it shares practically no homology (except for a few low hits limited to the RING domain) with any organism outside of fungi, and even in fungi the homology is rather low (100 – 200 bits) outside of Saccharomycetes.
Its function remains elusive, even after reading the interesting paper you linked. Its only known target seems to be CSE4p, a strange Histone H3 like protein, 229 AAs long. From Uniprot:
This strange variant seems, too, essentially restricted to Saccharomycetes, except for the partial homology (about 130 bits) to histone H3 in the C terminal part.
So, this complex biological system linked to yeast plasmids seems to be a remarkable example of taxonomically restricted complexity.
Involving, of course, ubiquitin! 🙂
DATCG at #259:
I agree with you that protein nomenclature is often misleading. Proteins that are clear homologues in many organisms receive often a lot of different names. You can find that multitude of names in their Uniprot record, usually.
For example, our much discussed p97 is reported in Uniprot, for humans, as:
TERA_HUMAN: Transitional endoplasmic reticulum ATPase
But also:
TER ATPase
VCP: Valosin-containing protein
15S Mg(2+)-ATPase p97 subunit
and we know that, in yeast, it is called:
CDC48: Cell division control protein 48
In papers, you can often find those different names, and it can be difficult sometimes to understand that some papers are referring to the same protein!
And, in this case, we are talking of a very conserved protein, and there can be no doubt that human TERA and yeast CDC48 are homologues, because they share 1178 bits and 68% identities and 83% positives.
DATCG, Dionisio:
Again our friend TERA/VCP/p97/CDC48, in some new role! 🙂
The following paper is of January 2018:
Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798933/
(Public access)
Mitochondrial fusion?
Yes, because we learn that:
If someone reading this thread is starting to believe that I am probably making up things, I am certainly not offended! 🙂
gpuccio @276:
Yes, it seems like “fake news” indeed. 🙂
For over a century, the abnormal movement or number of centrosomes has been linked with errors of chromosomes distribution in mitosis. While not essential for the formation of the mitotic spindle, the presence and location of centrosomes has a major influence on the manner in which microtubules interact with the kinetochores of replicated sister chromatids and the accuracy with which they migrate to resulting daughter cells. A complex network has evolved to ensure that cells contain the proper number of centrosomes and that their location is optimal for effective attachment of emanating spindle fibers with the kinetochores. The components of this network are regulated through a series of post-translational modifications, including ubiquitin and ubiquitin-like modifiers, which coordinate the timing and strength of signaling events key to the centrosome cycle. In this review, we examine the role of the ubiquitin system in the events relating to centriole duplication and centrosome separation, and discuss how the disruption of these functions impacts chromosome segregation.
Zhang, Ying, and Paul J. Galardy. “Ubiquitin, the Centrosome, and Chromosome Segregation.” Chromosome Research 24, no. 1 (January 2016): 77–91. https://doi.org/10.1007/s10577-015-9511-7.
https://www.researchgate.net/profile/Paul_Galardy/publication/287971598_Ubiquitin_the_centrosome_and_chromosome_segregation/links/5759653208ae9a9c954ed1f7/Ubiquitin-the-centrosome-and-chromosome-segregation.pdf
Post-translational modification of proteins by ubiquitylation is increasingly recognised as a highly complex code that contributes to the regulation of diverse cellular processes. In humans, a family of almost 100 deubiquitylase enzymes (DUBs) are assigned to six subfamilies and many of these DUBs can remove ubiquitin from proteins to reverse signals. Roles for individual DUBs have been delineated within specific cellular processes, including many that are dysregulated in diseases, particularly cancer. As potentially druggable enzymes, disease-associated DUBs are of increasing interest as pharmaceutical targets. The biology, structure and regulation of DUBs have been extensively reviewed elsewhere, so here we focus specifically on roles of DUBs in regulating cell cycle processes in mammalian cells. Over a quarter of all DUBs, representing four different families, have been shown to play roles either in the unidirectional progression of the cell cycle through specific checkpoints, or in the DNA damage response and repair pathways. We catalogue these roles and discuss specific examples. Centrosomes are the major microtubule nucleating centres within a cell and play a key role in forming the bipolar mitotic spindle required to accurately divide genetic material between daughter cells during cell division. To enable this mitotic role, centrosomes undergo a complex replication cycle that is intimately linked to the cell division cycle. Here, we also catalogue and discuss DUBs that have been linked to centrosome replication or function, including centrosome clustering, a mitotic survival strategy unique to cancer cells with supernumerary centrosomes.
Darling, Sarah & Fielding, Andrew & Sabat-Po?piech, Dorota & Prior, Ian & Coulson, Judy. (2017). Regulation of the cell cycle and centrosome biology by deubiquitylases. Biochemical Society Transactions. 45. BST20170087. 10.1042/BST20170087.
http://www.biochemsoctrans.org.....l-text.pdf
DATCG and gpuccio,
Please, be alert for repeated references. I may have messed up some required steps in the Zotero rules, causing some papers to get posted twice by mistake. Just raise a red flag if you notice such a case. Thanks.
Ubiquitin-specific protease 15 (USP15) is a widely expressed deubiquitylase that has been implicated in diverse cellular processes in cancer. Here we identify topoisomerase II (TOP2A) as a novel protein that is regulated by USP15. TOP2A accumulates during G2 and functions to decatenate intertwined sister chromatids at prophase, ensuring the replicated genome can be accurately divided into daughter cells at anaphase. We show that USP15 is required for TOP2A accumulation, and that USP15 depletion leads to the formation of anaphase chromosome bridges. These bridges fail to decatenate, and at mitotic exit form micronuclei that are indicative of genome instability. We also describe the cell cycle-dependent behaviour for two major isoforms of USP15, which differ by a short serine-rich insertion that is retained in isoform-1 but not in isoform-2. Although USP15 is predominantly cytoplasmic in interphase, we show that both isoforms move into the nucleus at prophase, but that isoform-1 is phosphorylated on its unique S229 residue at mitotic entry. The micronuclei phenotype we observe on USP15 depletion can be rescued by either USP15 isoform and requires USP15 catalytic activity. Importantly, however, an S229D phospho-mimetic mutant of USP15 isoform-1 cannot rescue either the micronuclei phenotype, or accumulation of TOP2A. Thus, S229 phosphorylation selectively abrogates this role of USP15 in maintaining genome integrity in an isoform-specific manner. Finally, we show that USP15 isoform-1 is preferentially upregulated in a panel of non-small cell lung cancer cell lines, and propose that isoform imbalance may contribute to genome instability in cancer. Our data provide the first example of isoform-specific deubiquitylase phospho-regulation and reveal a novel role for USP15 in guarding genome integrity.
Fielding, Andrew & Concannon, Matthew & Darling, Sarah & V. Rusilowicz-Jones, Emma & Sacco, Joseph & Prior, Ian & J. Clague, Michael & Urbé, Sylvie & Coulson, Judy. (2018). The deubiquitylase USP15 regulates topoisomerase II alpha to maintain genome integrity. Oncogene. 10.1038/s41388-017-0092-0.
https://www.researchgate.net/publication/323127826_The_deubiquitylase_USP15_regulates_topoisomerase_II_alpha_to_maintain_genome_integrity/fulltext/5a81cb2aa6fdcc6f3ead658d/323127826_The_deubiquitylase_USP15_regulates_topoisomerase_II_alpha_to_maintain_genome_integrity.pdf
Deregulation of centriole duplication has been implicated in cancer and primary microcephaly. Accordingly, it is important to understand how key centriole duplication factors are regulated. E3 ubiquitin ligases have been implicated in controlling the levels of several duplication factors, including PLK4, STIL and SAS-6, but the precise mechanisms ensuring centriole homeostasis remain to be fully understood. Here, we have combined proteomics approaches with the use of MLN4924, a generic inhibitor of SCF E3 ubiquitin ligases, to monitor changes in the cellular abundance of centriole duplication factors. We identified human STIL as a novel substrate of SCF-?TrCP. The binding of ?TrCP depends on a DSG motif within STIL, and serine 395 within this motif is phosphorylatedin vivoSCF-?TrCP-mediated degradation of STIL occurs throughout interphase and mutations in the DSG motif causes massive centrosome amplification, attesting to the physiological importance of the pathway. We also uncover a connection between this new pathway and CDK2, whose role in centriole biogenesis remains poorly understood. We show that CDK2 activity protects STIL against SCF-?TrCP-mediated degradation, indicating that CDK2 and SCF-?TrCP cooperate via STIL to control centriole biogenesis.
Arquint, Christian & Cubizolles, Fabien & Morand, Agathe & Schmidt, Alexander & Nigg, Erich. (2018). The SKP1-Cullin-F-box E3 ligase ?TrCP and CDK2 cooperate to control STIL abundance and centriole number. Open Biology. 8. 170253. 10.1098/rsob.170253.
https://www.researchgate.net/profile/Alexander_Schmidt3/publication/323170017_The_SKP1-Cullin-F-box_E3_ligase_bTrCP_and_CDK2_cooperate_to_control_STIL_abundance_and_centriole_number/links/5aa1389da6fdcc22e2d10921/The-SKP1-Cullin-F-box-E3-ligase-bTrCP-and-CDK2-cooperate-to-control-STIL-abundance-and-centriole-number.pdf
#267
“Yes, but unfortunately sometimes it’s easier to buid something again than to repair it.”
Oh, like what you’re pointing out. So, “naturally” speaking or by Design, we have multiple routes to organized redistribution and/or total destruction of proteins.
The Proteaosome itself is not total destruction of all cellular matter, correct? It’s not a garbage disposal per say as an apt analogy? The proteins, misfolded, etc., go in and are broken down to component parts that can then be recycled for new parts, correct?
I’m bypassing or leaving out the full spectrum. But there’s apoptosis and other methods as well.
To add, we are expected to believe that a system decision like this – to prevent proteolysis, or to allow, then recycle is by a blind, unguided RM & NS “process.”
“The problem with neoplastic cells is that, once the initial transformation takes place, a lot of further mutations or functional impairments is very likely to follow.”
Agree!
“That’s also the reason for resistance to therapy in relapsed neploasias.”
Agree again, so my question is, what is correctly terminology for molecular biology? I used “upstream” for me meaning to a) detect, b) correct the problem prior to neoplasia. Is that to difficult? Is the current process that corrects missing critical points of mutation? And can it be… hmmm, helped to recognize them?
I may be assuming to much to take on here from an overall systems perspective.
Dionisio, you are on a roll 🙂
LOL @RollingStone reference.
ah, educational portal of PDB
http://pdb101.rcsb.org/browse
and NCBI’s 3D viewer..
https://www.ncbi.nlm.nih.gov/Structure/icn3d/full.html?complexity=3&buidx=1&showseq=1&mmdbid=60755
Playing devil’s advocate since we have no participation by opponents to Design in favor of a blind, unguided “process,” I’m putting my Hunter-cap on. You may want to Google it. 😉
(ps if this is considered to off-topic we can discuss another time)
The challenge..
“The hslV protein has been hypothesized to resemble the likely ancestor of the 20S proteasome.HslV is generally not essential in bacteria, and not all bacteria possess it, while some protists possess both the 20S and the hslV systems.”
So, is hslV a possible ancestor to 20S Proteasome? Could it be? Might it be?
These scientist may have found a likely candidate which might be related to an ancestral gene, which could be a breakthrough in understanding the possible evolution of the Proteasome by natural sequence of events by a gradual process of random mutations and natural selection.
Evolution of Proteasome Regulators in Eukaryotes
#267 Gpuccio, follow-up to 287,
I may be asking wrong questions and mistaken on pathways to tumor cells. If so, it explains my confusion of a Proteasome “lockout” solution to stop cancer cells from growing and elimination of them. I do recognize it is a solution, but was thinking there might be more efficient methods with less side effects in treatment of multiple myeloma by Kyprolis. As an example, but no means trying to target any specific medication.
Certainly it works in a certain percentage of patients.
But it can lead to other consequences in patients. So it’s knocking out one problem, but creating another.
I don’t know of better solutions, but thinking if we were to look at the different pathways to the cancerous cells, what logical points along the way would we find the breakdown(deleterious mutations) and then see if there’s an alternative solution to a blocking attempt in the proteasome. Maybe a recognition of mutation prior to the signal for degradation is a way. Not easy, but maybe in breakdown of systems immunity, there’s a missing conditional check of mutations by error correction.
Is it even feasible to think of adding such a new “check” for error correction. And then what would be downside of doing so.
If there’s a SNP, point mutation, or… well, in searching came across this a Stop Codon mutation and a way to correct it in research done in Yeast.
It’s a fairly good review of why this is so difficult as well.
http://sitn.hms.harvard.edu/flash/2011/issue97/
These are broad and difficult questions I know or researchers would already have these answers.
follow up to #290…
Recognizing different solutions may or may not be advantageous dependent upon different mechanisms within cells and error correction features.
I was thinking one reason to use Error Correction is it already exist as a functional step.
It would be like adding another Conditional Check? Maybe.
But recognize researchers do not know all the steps to simply add a new check feature(or override) at this time. Nor do researchers know all the rules especially in human cells. But the Harvard article gives me hope.
Gpuccio,
I am reminded now of your Open Access paper you referenced at #89, Ubiquitin Enzymes in the Regulation of Immune Responses
and Figure 3… 😉
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490640/figure/F0003/
So, yeah, whew… trying to impact these steps, rules interactions is mind boggling.
So we have, trying to think through this multiple checks and balances on disease fighting systems, heavily regulated by Ubiquitin Systems and DUBS, etc.
Maybe I’ve conflated the two in my rush to think of different solutions. Though I’m guessing SNPs can cause problems for E1, E2, and E3 steps breaking down, then the cascade of steps following.
OK, apologies for going to far off topic.
Dionisio at #278 and 279:
These two processes of ERAD (ER-associated degradation, with associated retrotranslocation) and Mitochondrial fusion are really surprising.
They are both critically dependant on an unexpected dynamin plasticity of membranes in inner organelles. I am not suprised at all, instead, that the related mechanisms and controls remain “poorly understood” or “elusive”.
But ubiquitin certainly a major role in both.
Now, that’s really, really weird! That the same regulation system, which is in itself as complex and multi-faceted as we have seen in this thread, can at the same time be the key regulator in such different processes (together with all the others we have discussed) is IMO mind-blogging.
I really cannot imagine any way to put such a system to work with any bottom-up strategy, even if designed. You really need a strict top-down engineering to get that kind of results. And even then, you need an unbelievable attention to details and connections between systems, and a perfect control of the symbolic system you are using.
The cross-talk between inner compartments in the cell is really a fascinating issue: too often we think of the cell as some rather homogeneous environment, or we just acknowledge the separation between nucleus and cytoplasm in eukaryotes. But the cytoplasm is anything but homogeneous. Organelles are separated by membranes, and membranes, as we have seen, are dynamic tools which are almost magically shaped and reshaped by complex molecular systems.
And, even where mebranes are not present, a lot of functional sub-sections can be dynamically assessed, continuosly created and destroyed, shaping a functional landscape of cytoplasmic events which we still have to start to understand: second messengers, signaling pathways, and so on. No part of cytoplasm is the same as any other, each landscape is unique and functional.
See, for example, here:
Membrane-bound organelles versus membrane-less compartments and their control of anabolic pathways in Drosophila
https://www.sciencedirect.com/science/article/pii/S0012160617300131
(Public access)
Dionisio, Gpuccio,
When I began looking at ERAD, and translocation, or retrotranslocation, I was like, wow, wow, wow… when you posted on retroChaperones.
Great papers Dionisio, now when is there time to review all of these ubiquitin-related networks and functions?
🙂
#293 Cpuccio, interesting…
It is nevertheless emerging that cell compartmentalization is also achieved by steady-state membrane-less assemblies in the nucleus, such as nucleoli, Cajal bodies and nuclear speckles, and in the cytoplasm, such as RNA based C. elegans P-granules, P-bodies, ribosomes, as well as others that do not contain RNA, like centrosome, proteasome and aggresome (Rajan et al., 2001).
In this case, what is “steady-state” referring too?
Also, here is “intrinsically disordered domains”
Then ubiquitination…
Reaction to stress, creation of stress induced solutions, reversible(!) after stress period is finished.
Amazing stuff!
And this all done in “compartment-less” area through what I assume is unique solution? Not sure if this is replicated in prokaryotes? Or, unique to eukaryotes?
Great thing is, if it’s designed, molecular engineers, communications and network engineers, coders, etc., can reverse engineer it 🙂 Which is why Design Theory is a better heuristic going forward!
Darwin is dead, neo-Darwinism is too as an overall solution guide, and only ancillary mutations it appears, mostly deleterious or weak form of survival mechanism.
oh wow…
Yep a system spontaneously generated with stress reaction mediation and then dispersion and back to normal.
Sure… from abiogenesis to coordinated systems networking.
off-topic,
lncRNA treatments, although I assume, somewhere ubiquitin is in the pudding 😉
Epigenetics, what once was thought to be Junk turns out to be crucial for optimized health and a key part of solving health issues.
http://www.frontlinegenomics.c.....ng-cancer/
DATCG,
FYI – the prolific Italian composer GP got another ‘song’ in the ‘hit parade’ top 5 in the first 3 weeks since its release!
This is interesting because the ‘pure science’ genre doesn’t seem very popular in this world. Who are those anonymous readers?
🙂
DATCG @294:
“…is there time to review all of these ubiquitin-related networks and functions?”
Good question.
Have you heard of the “Big Data Problem in Biology”?
#297 Curious Bio-technophiles maybe? 😉
Woot, wooot… Which reminds me, I was going to post something the other day on ER and celluar structures – organelles and your postings reminded me, I like pictures 😉 or videos.
And I’m guessing some readers and lurkers do as well. There are many fine examples on youtube, but this is a good start and people can then see all the other choices should they like to learn more refined knowledge of each structure. This video shows Eukaryote and Prokaryote cells. Including a special guest performance by the irreducibly complex flagella 😉
https://www.youtube.com/watch?v=URUJD5NEXC8
Protein Synthesis…
https://www.youtube.com/watch?v=kmrUzDYAmEI
and maybe more later.
#298-188… I think someone mentioned it before 😉
Might be a good job to get into, high demand 😉 and good pay for sure!
#297 Dionisio,
and congrats to the systems ID review to the Mastro Gpuccio for another Top 5 composition 🙂
Ubiquitin Chain formation, simplified overview shown by Fun with Tinker toys, multiple Chain positions…
https://www.youtube.com/watch?v=miZYmuDKO2s
Lecture in below video on Ubiquitin and Autophagy, can go to minute 4.20 mark for a quick look.
Lecturer states about 90% of proteins are controlled by one of these two systems. Main message for good health? Don’t stop exercising!
Resting for to long activates the proteolytic systems of Ubiquitin and autophagy! Muscles become weaker…. as Contractile Proteins are removed.
https://www.youtube.com/watch?v=tliw477USx0
Dionisio, DATCG:
“FYI – the prolific Italian composer GP got another ‘song’ in the ‘hit parade’ top 5 in the first 3 weeks since its release!”
Well, it would have been impossible without your constant support! 🙂
“This is interesting because the ‘pure science’ genre doesn’t seem very popular in this world. Who are those anonymous readers?”
Maybe we are in some kind of niche market…
DATCG at #302:
The thing I like most in the Tinker toys video is how she tries to be as precise as possible in wrapping the string around the wooden nucleosome, so that it is more or less 1.67 turns! (OK, more or less…) 🙂
#304, hahahaha… you caught that did you? 😉
here’s a image representation of our little friend Cdc48, ubiquitin, retrotranslocation complex, proteasome, ERAD-C & ERAD-L
no tinker toys here 😉 She would have to bring a bigger box!
http://www.cell.com/cms/attach.....46/gr3.jpg
and interestingly, another representation from August 2014 of threading and Cdc48 regulation to the proteasome. Notice all the Question Marks at end of each explanation. Not sure if that’s an error or just a valid – we don’t know for sure…
http://www.mdpi.com/cells/cell.....824-ag.png
and the associated paper…
Regulation of Endoplasmic Reticulum-Associated Protein Degradation (ERAD) by Ubiquitin
http://www.mdpi.com/2073-4409/3/3/824/htm
#303,
“Maybe we are in some kind of niche market…”
not by accident, only by Design 😉
BTW, many readers might be searching for these papers we have all listed and come across this site as well. I’ve noticed several times UD gets listed fairly high, even on 1st page organic search sometimes on past references. Of course the searches are usually highly specific, long-tail SEO type searches.
Special Issue “Protein Ubiquitination” 14 papers… published 2014.
http://www.mdpi.com/journal/ce.....uitination
One of interest is:
Versatile Roles of K63-Linked Ubiquitin Chains in Trafficking
Zoi Erpapazoglou 1,2, Olivier Walker 3 and Rosine Haguenauer-Tsapis 1,*
http://www.mdpi.com/2073-4409/3/4/1027
Abstract
Keywords of the publication:
– ubiquitin
– ubiquitin chain
– Sumo
– 26S proteasome
– protein stability
– protein localization
– E3 ligases
– cellular regulation
– signal transduction
– development
Example of Trafficking Steps involving UbK63 chains…
http://www.mdpi.com/cells/cell.....7-g002.png
.
Gpuccio, a bit off topic again, but thought it’s related as well in so many ways as we keep being amazed by all the intricate interactions and interdependency of so many systems working, coordinating together with Ubiquitin and multiple functions of different genes and proteins.
When I came across this, made me think of you and TFs. And this shows TF’s constrain evolution.
Transcription Factors, Pleiotropy and Constraints on Evolution
hattip: Jeffery Tompkins PhD – ICR.org
My overall thoughts are there are Constraints, conserved regions and hot spots meant for rapid evolution according to environmental queues, or stress, but very limited in novel forms. Like finch beaks. Sure, they get large or small based upon seasons, rain, droughts, but overall body plan, the bird is still a bird.
And I simply cannot imagine the Ubiquitin System allowing for much more change.
What level of constraint is the Ubiquitin System on evolution? And how would that begin to be measured? Cross-posted this here at UD post:
Best guesses fail with plant evolution
DATCG @308:
“[…] there are Constraints, conserved regions and hot spots meant for rapid evolution according to environmental queues, or stress, but very limited in novel forms.”
environmental queues?
huh?
did you mean “cues”?
gpuccio @293:
Agree. Beyond fascinating.
DATCG at #308:
Very interesting paper about TFs and their evolutionary rate!
I think the really interesting data is in Fig. 2A, where it is shown that the evolutionary pattern of TFs, as referred to the whole molecule, is strongly related to the number of known TF -TF interactions.
The analysis here is done with 1552 TFs, and it is a linear regression, but I suppose that a p value of 5e-36 can never be questioned by anybody! 🙂
That is the true, strong point: TFs which have a high number of interactions with other TFs are highly contrained (IOWs, their whole sequence is strongly conserved).
A few comments:
a) Just as a clarification for possible readers, the parameter they are using to measure sequence conservation is the dN/dS ratio, which is nothing else than the Ka/Ks ratio (against, nomenclature!) that I have often used in my discussions, IOWs the ration between non synonimous mutations (per non synonimous site) and synonimous mutations (per synonimous site). The lower this value, the higher the sequence conservation. The reference to synonimous mutations makes the measure relatively independent from evolutionary times (at least for evolutionary times which are not too long).
b) I am not too sure that the number of TF – TF interactions can be interpreted only as a measure of pleiotropy, IOWs of multiple function. As the working of TFs for one single function is often combinatorial, with many TFs joining in very big protein complexes to achieve the fine tuning of the function itself, I would say that the number of known TF – TF interactions is also a measure of the complexity of the individual functions regulated by those TFs, and not only of the number of functions to which each TF contributes.
c) The important point is: TFs are highly functional molecules, and their whole molecule contributes to their function, not only the DBD, or even the known protein interaction domains. As we have seen, the sequences with “conditional folding” are probably the most important in the final regulatory functions.
DATCG at #307:
Great review of the known roles of K63 ubiquitin chains, “the second most abundant form of ubiquitylation”!
This kind of ubiquitination is specially interesting because it is usually proteasome independent (K48 and K11 being the proteasome linked ubiquitinations).
And look at the number of intriguing and complex functions implemented by K63 ubiquitination: modifications of plasma membrane proteins and cargoes, internalization of receptors, sorting to multivesicular bodies, other forms of cell trafficking, signaling pathways, selective autophagy, mitophagy, xenophagy.
These are just the main titles of the various sections in the paper, where each of these complex subjects is well summarized according to our present understanding.
And all these functions must be added to the multitude of specific functions that the ubiquitin system implements by K48 ubiquitination and proteosamal degradation, as we have discussed in detail previously! 🙂
Dionisio at #317:
Yes, ubiquitin like proteins certainly add a lot to the complexity of the system. And the paper you linked is a very good and very recent review of what is known about them.
SUMO is one of the most important in the group.
SUMO1 is a 101 AAs long protein in humans. Strangley, it does not exhibit a great sequence homology with ubiqutin (13 identities, 33 positives, 29.3 bits, a weakly significant e-value of 9e-07).
However, its sequence is highly conserved in eukaryotes. Not so much as ubiquitin, but highly conserved just the same.
The human protein shows 47 identities and 66 positives with fungi (102 bits, e value 2e-27). But those values of homology rapidly increase in metazoa.
The protein is one of those which undergo important engineering in vertebrates, passing from 138 to 178 bits of homology, a 0.396 baa jump.
The protein in cartilaginous fish shows 84% identities and 92% positives with the human form. This is very strong conservation.
So, the obvious point is: SUMO is an ubiquitin-related protein, but it is different: different in sequence, different in functions and functional networks. It has its specific E1-E2-E3 systems.
And this “different” protein is already present in single celled eukaryotes, and is well conserved throughout the whole eukaryotic history. Much more conserved than it is similar to ubiquitin itself.
So, what does that mean? It means that this is certainly a variant of the ubiquitin concept, but it appears from the beginning and is different form the beginning, and it maintains its difference, because its difference is functional, is specific, and is therefore conserved.
gpuccio @320:
“[…] this is certainly a variant of the ubiquitin concept, but it appears from the beginning and is different form the beginning, and it maintains its difference, because its difference is functional, is specific, and is therefore conserved.”
Interesting. Thanks.
is this off-topic? not sure…
@327:
Perhaps this is a case where the meaning of the term “evolution” is unanimously accepted? 🙂
Evolution of our understanding of ubiquitin?
maybe the functional complexity of cellular* membranes could be a future topic for an OP?
(*) including organelle membrane too
https://www.ncbi.nlm.nih.gov/Structure/pdb/6BMF
https://www.ncbi.nlm.nih.gov/Structure/pdb/6AP1
Dionisio,
“… queue” is a word I abuse quite frequently. Think it is a leftover from many visits to London and parts of England and Scotland where I had to stand in a queue 🙂
For some reason my brain mistranslates cue to queue. Not the first time. Maybe I’ll just use a different word entirely.
Environmental Factors 😉 EFs. or Input.
Layman, Awo A. K., and Paula M. Oliver. “Ubiquitin Ligases and Deubiquitinating Enzymes in CD4 + T Cell Effector Fate Choice and Function.” The Journal of Immunology 196, no. 10 (May 15, 2016): 3975–82. https://doi.org/10.4049/jimmunol.1502660.
Skieterska, Kamila, Pieter Rondou, and Kathleen Van Craenenbroeck. “Regulation of G Protein-Coupled Receptors by Ubiquitination.” International Journal of Molecular Sciences 18, no. 12 (April 27, 2017): 923. https://doi.org/10.3390/ijms18050923.
Ohtake, Fumiaki, Hikaru Tsuchiya, Yasushi Saeki, and Keiji Tanaka. “K63 Ubiquitylation Triggers Proteasomal Degradation by Seeding Branched Ubiquitin Chains.” Proceedings of the National Academy of Sciences 115, no. 7 (February 13, 2018): E1401–8. https://doi.org/10.1073/pnas.1716673115.
Grice, Guinevere L., and James A. Nathan. “The Recognition of Ubiquitinated Proteins by the Proteasome.” Cellular and Molecular Life Sciences 73, no. 18 (September 2016): 3497–3506. https://doi.org/10.1007/s00018-016-2255-5.
Poot, Stefanie A.H. de, Geng Tian, and Daniel Finley. “Meddling with Fate: The Proteasomal Deubiquitinating Enzymes.” Journal of Molecular Biology 429, no. 22 (November 2017): 3525–45. https://doi.org/10.1016/j.jmb.2017.09.015.
Boutouja, Fahd, Rebecca Brinkmeier, Thomas Mastalski, Fouzi El Magraoui, and Harald Platta. “Regulation of the Tumor-Suppressor BECLIN 1 by Distinct Ubiquitination Cascades.” International Journal of Molecular Sciences 18, no. 12 (November 27, 2017): 2541. https://doi.org/10.3390/ijms18122541.
Dionisio @ 327/331
Ha! 🙂
As knowledge increases of Functional Sequence Complex – inter-Dependent Organized Systems(FSC-iDOS), I think we find “evolve” is an over-hyped term in “evolutionary” biology.
Gpuccio always points out Variation? Random Variation.
There is deleterious mutations and then significantly controlled, programmatic, conditional logic of Allowed Variation. Based off environmental qu…. uh stimuli 😉
Or internal factors with prescribed actionable network systems response.
All the papers you posted and Gpuccio commented on shows overwhelming evidence of Design and planning. At so many different levels of expertise, not only coding, but of engineering which as you’ve said, we’ve not seen nothing yet!
Like “junk” DNA, functions abound in places Darwinist once said had no function…
Appendix Might Save Your Life – 2012 SciAm
“Evolve” “Junk” “Vestigial”
You keep using that word, I do not think it means what you think it means
.
Ran a quick search on technology and Ubiquitin to determine how far science and scientist have “evolved” in use of technology to decode the Ubiquitin Code.
Tracing down linear ubiquitination
New technology enables detailed analysis of target proteins
Date: March 20, 2017
Source: Goethe University Frankfurt
Summary: Researchers have developed a novel technology to decipher the secret ubiquitin code.
Only a year ago this technique began. Amazing. So many, many more papers to come in future using this technique of identification.
Great work by Dr. Husnjak and his team(s) at Goethe University Frankfurt.
Katarzyna Kliza, Christoph Taumer, Irene Pinzuti, Mirita Franz-Wachtel, Simone Kunzelmann, Benjamin Stieglitz, Boris Macek & Koraljka Husnjak
Nature Methods volume 14, pages 504–512 (2017)
doi:10.1038/nmeth.4228
Scientific paper behind pay wall…
Nature – Internally tagged ubiquitin: a tool to identify linear polyubiquitin-modified proteins by mass spectrometry
Decipher:
1 – decode
1a – decipher a secret message
3a – to make out the meaning of despite indistinctness or obscurity
3b – to interpret the meaning of
Code:
3a – a system of signals or symbols for communication
3b – a system of symbols (such as letters or numbers) used to represent assigned and often secret meanings
4 – genetic code
5 – instructions for a computer (as within a piece of software
Dionisio at #131:
“Evolution of our understanding of ubiquitin?”
Well, our understanding of ubiquitin has certainly “evolved” from the beginning of this thread! 🙂
I suppose it was not a completely unguided process, however. It took some specific work and attempts at understanding by a small group of rather insubordinate people (including me), a lot of not really “natural” selection of papers from the literature, and some effort to express relevant thoughts in the 300+ comments by 4+ commenters in the discussion.
I would say that environmental pressure (comments from the other side) had no relevant role in shaping that evolution (indeed, no role at all!).
RV certainly was present, mostly in the form of typos, even if our small structure has a very efficient proof checking system (you know what I mean! 😉 )
That said, the results are not bad. And I can see a lot of convergent evolution all around! 🙂
Dionisio:
“Maybe the functional complexity of cellular* membranes could be a future topic for an OP?
(*) including organelle membrane too”
It’s certainly a possibility.
DATCG at #336:
“Or internal factors with prescribed actionable network systems response.”
The subject of intelligent and functional algorithmic responses to environment is fascinating. We have certainly many examples of that.
One is well known, and I have written about it in a previous OP:
https://uncommondescent.com/intelligent-design/antibody-affinity-maturation-as-an-engineering-process-and-other-things/
Antibody affinity maturation is indeed a wonderful example of algorithmic process which creates important functional information based on the acquisition of information from the environment (the contact with the antigen) and from a highly complex computational process (the maturation process), essentially of the bottom-up type.
It is interesting that many times it gas been pointed to as an example of “darwinian evolution”, which is good evidence of how confused are sometimes our kind interlocutors.
Of course, such a refined computational process is outstanding evidence of design: designed objects can indeed comput new information about the pre-defined function and using new information inputs and their pre-programmed computing information: that’s what computers, or neural networks, do all the time.
I think that another system designed to provide that kind of functionality is probably the plasmid system in prokaryotes.
However, computational systems, even computers, always have the same fundamental limit in themselves: they can only compute what they have been directly or indirectly programmed to compute, and nothing else.
That’s why the generation of really new complex functional information always requires a conscious designer.
DATCG at #336:
“All the papers you posted and Gpuccio commented on shows overwhelming evidence of Design and planning. At so many different levels of expertise, not only coding, but of engineering which as you’ve said, we’ve not seen nothing yet!”
Of course. We have been witnessing here, in this interesting thread, a perfect example of design of the highest kind, a kind that vastly outperforms anything we can yet try to conceive.
Just to sum up, we have seen tons of examples of:
a) Huge functional complexity, and of the highest type, the regulatory type.
b) The ubiquitous presence of refined semiosis, everywhere.
c) Hundreds, maybe thousands, of individual systems exhibiting, each of them, irreducible complexity.
But our kind interlocutors seem not to be interested in all that. OK, but they miss a lot of fun! 🙂
gpuccio @340:
Where are DNA_Jock, sparc, and other politely dissenting interlocutors that were so active in your interesting 2015 OP and discussion thread that you pointed at?
It would definitely add some “spice” to the discussion to have a couple of serious opponents actively participating, but where have they all gone? 🙂
Has anybody heard of professor Arthur Hunt lately?
I’m willing to get off this thread if that’s the condition for professor Larry Moran to come back. At least that would reassure him that nobody will ask dishonest questions with “tricky” words like “exactly” subliminally embedded in the questions. GP as the owner and moderator of this thread will ensure that all “tricky” words are written in bold font so nobody misses their presence in the text. 🙂
gpuccio @341:
Excellent summary! Thanks.
gpuccio @338:
Very refreshing sense of humor pointing to what’s going on here. Thanks.
I have learned (and still learning) much from this OP + discussion thread. Much more than I expected at the start, even though my expectations were high. Thanks.
gpuccio @339:
That’s encouraging. I look forward to reading it someday. Thanks.
BTW, are your OPs part of your intensive preparation for a potentially future OP on “procedures”?
As UB stated before, if you ever decide to write a book with all your OP + follow up comments, you’ll make many happy campers around here and out there! 🙂
gpuccio @338:
To illustrate the refreshingly funny assessment of this discussion and its effect on our knowledge, let’s add that around 120 papers have been referenced in this thread so far.
Dionisio:
“BTW, are your OPs part of your intensive preparation for a potentially future OP on “procedures”?”
I suppose they are. I must say that the “preparation” is much more “intensive” than I could imagine! 🙂
Dionisio:
“To illustrate the refreshingly funny assessment of this discussion and its effect on our knowledge, let’s add that around 120 papers have been referenced in this thread so far.”
Yes. Not bad.
And, I would say, almost all rather pertinent. And many of them extremely recent.
Dionisio:
“It would definitely add some “spice” to the discussion to have a couple of serious opponents actively participating, but where have they all gone?”
I would like to know. Some of them were pretty good!
“Has anybody heard of professor Arthur Hunt lately?”
Apparently not.
“I’m willing to get off this thread if that’s the condition for professor Larry Moran to come back.”
I don’t believe that it would work! 🙂
I don’t think that I have ever discussed directly with Larry Moran, even if I have commented about some of his statements a couple of times.
“GP as the owner and moderator of this thread will ensure that all “tricky” words are written in bold font so nobody misses their presence in the text.”
Well, I have never “moderated” anything in my life, I would not like to begin with you! 🙂
I confide in your self-discipline to ensure that all bolds are assigned in a politically correct way.
DATCG at #337:
Wonderful clarification of terms which are often badly used.
It’s refreshing to see how the subjective experience of meaning is central even in simple definitions. And how the symbolic nature of codes is crystal clear in language.
Codes and design are connected just from the beginning by their definitions themselves: both words have no sense if we don’t refer in some way to the subjective experience of understanding meanings!
Chapard, C., P. Meraldi, T. Gleich, D. Bachmann, D. Hohl, and M. Huber. “TRAIP Is a Regulator of the Spindle Assembly Checkpoint.” Journal of Cell Science 127, no. 24 (December 15, 2014): 5149–56. https://doi.org/10.1242/jcs.152579.
Hoffmann, Saskia, Stine Smedegaard, Kyosuke Nakamura, Gulnahar B. Mortuza, Markus Räschle, Alain Ibañez de Opakua, Yasuyoshi Oka, et al. “TRAIP Is a PCNA-Binding Ubiquitin Ligase That Protects Genome Stability after Replication Stress.” The Journal of Cell Biology 212, no. 1 (January 4, 2016): 63–75. https://doi.org/10.1083/jcb.201506071.
Ma, Xingjie, Junjie Zhao, Fan Yang, Haitao Liu, and Weibo Qi. “Ubiquitin Conjugating Enzyme E2 L3 Promoted Tumor Growth of NSCLC through Accelerating P27kip1 Ubiquitination and Degradation.” Oncotarget 8, no. 48 (October 13, 2017). https://doi.org/10.18632/oncotarget.20449.
Min, M., T. E. T. Mevissen, M. De Luca, D. Komander, and C. Lindon. “Efficient APC/C Substrate Degradation in Cells Undergoing Mitotic Exit Depends on K11 Ubiquitin Linkages.” Molecular Biology of the Cell 26, no. 24 (December 1, 2015): 4325–32. https://doi.org/10.1091/mbc.E15-02-0102.
Nath, Somsubhra, Taraswi Banerjee, Debrup Sen, Tania Das, and Susanta Roychoudhury. “Spindle Assembly Checkpoint Protein Cdc20 Transcriptionally Activates Expression of Ubiquitin Carrier Protein UbcH10.” Journal of Biological Chemistry 286, no. 18 (May 6, 2011): 15666–77. https://doi.org/10.1074/jbc.M110.160671.
Iimura, Akira, Fuhito Yamazaki, Toshiyasu Suzuki, Tatsuya Endo, Eisuke Nishida, and Morioh Kusakabe. “The E3 Ubiquitin Ligase Hace1 Is Required for Early Embryonic Development in Xenopus Laevis.” BMC Developmental Biology 16, no. 1 (December 2016). https://doi.org/10.1186/s12861-016-0132-y.
Kai, Masatake, Naoto Ueno, and Noriyuki Kinoshita. “Phosphorylation-Dependent Ubiquitination of Paraxial Protocadherin (PAPC) Controls Gastrulation Cell Movements.” Edited by Jung Weon Lee. PLOS ONE 10, no. 1 (January 12, 2015): e0115111. https://doi.org/10.1371/journal.pone.0115111.
#340 Gpuccio,
After going back to 2015 post, I must have landed in a Wagner Hyper-astronomical subspace. Ha!
grrr… lost my original comment Wagner’s hypercube somewhere 😉 and no amount of steps to find it!
That was some fun reading! 🙂 I went back into dimensional subspace where everything was connected by a single step 😉
I see the light now, one step here, another there and voila from pink kittens to pink unicorns!
What was so funny is using Wagner as a defense laid open the failures of neo-Darwinism. Yet the claim was self-organization and hypothetical dimensions solve the very problem Darwinist claimed did not exist. Interesting!
Forgotten about that OP by you Gpuccio! Interesting look back! And even that I participated in it. Must have dropped off before the talk of astronomical library poofed into existence.
And today, here we are with more evidence that your positions are rock solid. And where is the blind, unguided hyper-astronomical solution?
We know Darwinism is dead, that Extended Synthesis is now at play in attempts to hold on to materialist doctrine. And neo-darwinism is dying on the vine as well, as some form of subset to whatever is next, hyper-astronomical libraries I guess.
That is desperation for sure. But then, maybe from the beginning so was Darwin’s attempt to write off Design by a series of gradual steps.
Dionisio, Gpuccio,
“Procedures” and future OPs?
What procedures? I’ve missed something after visiting hyper-astronomical dimensions.
DATCG:
Some time ago, I expressed my desire to write an OP about the problem of the “missing procedures”.
What I meant was (and is) that with all that we know about the genome, and I would add also about epigenetics, we see a wonderful display of intelligent coordination and differentiation of programs and of regulations, but in the end we don’t know where and how the real procedures that control all that are written.
In software, we have to write down the effectors, but we also need to write down the procedures that control the effectors.
In biological software, we know much about the proteins (the effectors), but we understand too little about what controls the ordered and differentiated manifestations of proteins (and other components) in all the various engineered outcomes that we see in cells: above all, the different types of cells and cellular states in multicellular beings.
Of course, today we know much more than yesterday. This same thread is evidence of that. And there is the huge fiels of epiganetics, which has added a lot of understanding.
And we know a lot also of cell differentiation. A lot more than we knew, certainly.
That’s the reason why I have renounced for the moment to deal with the problem of the missing procedures: I wanted to understand better what we know and what we don’t know. And, as I said to Dionisio, that has been, and is, a very “intensive preparation”.
Because what we know is really amazing. And what we don’t know is esponentially more than what we know.
However, I continue to believe that the procedures, those which are really essential, those which explain how things really work, are still missing. We know a lot of details, but we never understand what really controls the details.
The fact remains that in that elusive genome, with its 20000+ protein coding genes, and its non coding DNA, plus all the possible information in the cytoplasm or other epigenetic markings, there must be the information sufficient to guide all the various cell differentiations which lead to tissues and organs. And there must be a satisying answer to the problem of morphogenesis.
And there must be an answer to the architecure of systems like the immune system or, even worse, the nervous system of humans, for those who are not satisfied with the blind belief that a minor bundle of nucleotide variations in a few genes are enough to guide and determine the structure of 10^11 interconnected neurons, with all the advanced functions that, undeniably, the human brain seems to own.
Those are the missing procedures. I don’t think that we have any good idea of where and how that information is written. But I hope that, as we gather billions and billions of new details (the famous “Big data” problem), sooner or later some major breakthrough will take place.
Gpuccio,
Thanks, it’s a bit overwhelming, amazing and adventurous 🙂
I guess what we do know or can infer is it’s a Rules Based system, Modular and Conditional with massive amounts of parallel processing(billions of cells) and semiotic. The nervous system… whew…. back to being overwhelmed but in a good way 🙂
But as you point out…
Yes, many more details have come to light in just those few years since your 2015 post. And yet, so much more details to learn, remains! This is the great architecture of all systems in the world combined.
The Sensors and signals processing fascinates me as that is part of control, procedural and rules based. The control systems are massive. Once a sensor detects an aberration, it’s not enough to react. It must react, signal, monitor, then decide to keep reacting or stop the reaction – in case of immune systems defense. Or in any other case as we discussed on the balance of protein synthesis and degradation and recycling, a delicate balance.
I’ve been reading when I can about Sensors discovered in these or other processes. We know how important some systems are conserved. And we know why some are intentionally allowed to vary.
We need a Big Table of Rules and Conditions for Big Data.
Problem, Detection, Rules(If Then, Boolean, etc.), Signal, Proteins, Actions, Do-Until … Next Step
Maybe that’s just to simplified, but somehow all of these actions need to be codified, procedurally assigned and pattern checked.
Before I saw you and Dionisio discuss Procedures, an idea came that maybe one method of realization and visualization would be to track a specific change, damage, or protein life from start to finish across all systems interaction. From birth to death or recycling(degradation) in a cell?
And then codify the specific actions along the way, Step 1, 2, 3, 4… Detection, Alerts, Rules to Alerts, Actions to Take, etc.
Maybe Protein Synthesis, damage, repair, splicing, modification and eventual targeting for recycling. So far, all these excellent post by you from many different OPs has been looking at Modular Systems and Components. And those are overwhelming when we look at the multiplication of interactions like Ubiquitin. But if we dial it down to one specific point of functional interaction, then follow maybe it narrows down the thought process of uncovering procedures and rules?
Is that fair to say? Along with a variety of interactions of course that grow and influence them. Again, I may have missed some other post in the past.
Maybe it could be limited by intentional direction of steps. Leave out some conditional steps, maybe even whole steps at first and fill in those steps later. To keep it from being an overwhelming amount of information at once.
Even mark areas “unknown” or TBD(to be discovered).
Whatever we don’t know – will be fun to discover! Really appreciate all the efforts you provide and explanations. Thanks again. Looking back on your 2015 post was good to review.
And… now I jump to the Kinetochore 🙂
Which Dionisio first posted in Comment #22, then subsequent comments with differing roles of ubiquitin.
We live in amazing times where we enjoy all of this rich information available to us these days.
Here’s original video from 2012 starting 6 min mark of the Kinetochore broadcasting signals for eventual separation of chromosomes…
https://www.youtube.com/watch?v=WFCvkkDSfIU
Hope you guys had a great weekend.
here’s another “simple” animation for Damaged DNA and Repair from 2011…
DNA Damage Response to double-stranded DNA break — Homologous Recombination
And accompanying information summary of work flow. Check out all the ubiqutin tags and ubiquitin chains.
Well, that’s a load… for sure!
.
DATCG at #355:
Very good thoughts.
I really don’t know how the problem of Big Data and of overwhelming details can be treated to get a glimpse of the controlling procedures.
The problem in the end is to find where the information is.
Let’s take for example the fundamental problem of the transition from single celled organisms to multicellular. The problem could be summed up as follows: if I start with soem single celled organism, let’s say yeast, and I want to get a multicellular organism, let’s say c. elegans, what kind of information do I need to add? Is it all genomic? And what is it exactly?
Now, of course we know that yeast has “only” 6000 genes, while c. elegans has almost 20000. But the mere number of genes is not a good parameter, considering for example that some other fungus, like Phanerochaete chrysosporium, has almost 12000, and that drosophila has 13600, while humans themselves are at about 20000. The nubler of genes is not a good answer.
Non coding DNA is probably better, but of course it is still difficult to understand the role of great part of it.
Epigenetic states can keep a lot of information, but are they dependent on genomic information? Or can they store supplementary information which is tgransmitted directly, and does not rely on genomic stoiring?
In the end, we know that the information, whatever its form, must be in some way connected to the physical organism that reproduces, because there is no doubt that it is transmitted: otherwise, we could not explain how the miracles of function and differentiation take place each time, with remarkable precision.
I think we should probably consider a living being as a whole system, that includes genetic and epigenetic information which, at any moment, is in a dynamic state of interaction. The whole system probably bears the necessary information for life and reproduction and cell differentiation.
But that system could store infromation in many different ways, some of which we certainly have to discover yet, some of which could be very different from what we usually think of.
For example, I believe that we must go beyond the mere biochemical states, and look more deeply to what biophysics can tell us. We already know that for DNA biophysical states are complex and still poorly understood, and that they certainly have a major role in transcription regulation. The same can be said for proteins, especially considering what we have found about conditional folding, intrinsical disorder, and so on.
The same can be said for cellular states, including organelles and compartments, both membrane-linked and membraneless.
In a sense, the whole cell is a multi-faceted information system, that we still need to decode.
Extremely interesting, from this point of view, is the goldfish-carp experiment referenced in the Denis Noble video linked by Dionisio at #271, starting at mark 31:46, and whose original paper can be found here:
Cytoplasmic Impact on Cross-Genus Cloned Fish Derived from Transgenic Common Carp (Cyprinus carpio) Nuclei and Goldfish (Carassius auratus) Enucleated Eggs
https://academic.oup.com/biolreprod/article/72/3/510/2666963
And here is a follow-up, with interesting (and unexpected) news about mitochondria:
The carp–goldfish nucleocytoplasmic hybrid has mitochondria from the carp as the nuclear donor species
https://www.sciencedirect.com/science/article/pii/S0378111913016855?via%3Dihub
Here is a more general review:
The egg and the nucleus: a battle for supremacy
http://dev.biologists.org/cont.....ong#sec-10
And here, too:
Interspecies Somatic Cell Nuclear Transfer: Advancements and Problems
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787369/
gpuccio @358:
“In the end, we know that the information, whatever its form, must be in some way connected to the physical organism that reproduces, because there is no doubt that it is transmitted: otherwise, we could not explain how the miracles of function and differentiation take place each time, with remarkable precision.”
Oops! You used a politically incorrect word in scientific discussions: “miracles”
You better watch out! Next time, please refrain from using words like that. 🙂
DATCG at #356:
Great video!
The Kinetochore is certainly another incredible structure.
From Wikipedia:
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Dionisio:
“Oops! You used a politically incorrect word in scientific discussions: “miracles””
It’s an old problem. In my whole life, I have never been able to be politically correct! 🙂
DATCG at #357:
DNA repair: another key issue!
Just a curiosity: many of the proteins involved have a similar evolutionary history, more or less as can be seen in Fig. 5 in the OP for BRCA1, with a late development of the human sequenc