Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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Cell biology
Intelligent Design
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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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The ESCRT proteins are an ancient system that buds membranes and severs membrane necks from their inner face. Three "classical" functions of the ESCRTs have dominated research into these proteins since their discovery in 2001: the biogenesis of multivesicular bodies in endolysosomal sorting; the budding of HIV-1 and other viruses from the plasma membrane of infected cells; and the membrane abscission step in cytokinesis. The past few years have seen an explosion of novel functions: the biogenesis of microvesicles and exosomes; plasma membrane wound repair; neuron pruning; extraction of defective nuclear pore complexes; nuclear envelope reformation; plus-stranded RNA virus replication compartment formation; and micro- and macroautophagy. Most, and perhaps all, of the functions involve the conserved membrane-neck-directed activities of the ESCRTs, revealing a remarkably widespread role for this machinery through a broad swath of cell biology.
ESCRTs are everywhere. Hurley JH EMBO J. ;34(19):2398-407. doi: 10.15252/embj.201592484.

Complex complexity.Dionisio_{April 22, 2017
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The endosomal sorting complex required for transport (ESCRT), originally identified for its role in endosomal protein sorting and biogenesis of multivesicular endosomes (MVEs), has proven to be a versatile machinery for involution and scission of narrow membrane invaginations filled with cytosol. Budding of enveloped viruses and cytokinetic abscission were early described functions for the ESCRT machinery, and recently a number of new ESCRT functions have emerged. These include cytokinetic abscission checkpoint control, plasma membrane repair, exovesicle release, quality control of nuclear pore complexes, neuron pruning, and sealing of the newly formed nuclear envelope.
Novel ESCRT functions in cell biology: spiraling out of control? Campsteijn C, Vietri M, Stenmark H Curr Opin Cell Biol. 41:1-8. doi: 10.1016/j.ceb.2016.03.008

Complex complexity.Dionisio_{April 22, 2017
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Complex molecular machineries bud, scission and repair cellular membranes. Components of the multi-subunit endosomal sorting complex required for transport (ESCRT) machinery are enlisted when multivesicular bodies are generated, extracellular vesicles are formed, the plasma membrane needs to be repaired, enveloped viruses bud out of host cells, defective nuclear pores have to be cleared, the nuclear envelope must be resealed after mitosis and for final midbody abscission during cytokinesis. While some ESCRT components are only required for specific processes, the assembly of ESCRT-III polymers on target membranes and the action of the AAA-ATPase Vps4 are mandatory for every process. [...] we speculate how ESCRT-III and Vps4 might function together and highlight how the characterization of their precise spatiotemporal organization will improve our understanding of ESCRT-mediated membrane budding and scission in vivo.
ESCRT-III and Vps4: a dynamic multipurpose tool for membrane budding and scission. Alonso Y Adell M, Migliano SM, Teis D FEBS J. 283(18):3288-302. doi: 10.1111/febs.13688.

Complex complexity.Dionisio_{April 22, 2017
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Our knowledge on mechanisms that drive cargo sorting into EVs and uptake by recipient cells is limited. There is an urgent need for assays that monitor cargo delivery to target cells that are amenable to high throughput screening. The fast and accurate detection of aggregate induction in recipient cells will help to characterize general cellular pathways involved in aggregation and dissemination of protein aggregates.
Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates Shu Liu, André Hossinger, Sarah Göbbels & Ina M. Vorberg? Journal Prion Volume 11, Issue 2 Pages 98-112 http://dx.doi.org/10.1080/19336896.2017.1306162

Complex complexity.Dionisio_{April 21, 2017
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Many, if not all cells, release a repertoire of vesicles in the extracellular milieu. Secreted vesicles shed from the plasma membrane or produced by the endosomal system are collectively termed extracellular vesicles (EVs).? EVs are important mediators of intercellular communication and transfer proteins, RNAs and other cellular components between cells, thereby modulating diverse cellular processes in acceptor cells. As biomolecules incorporated into exosomes reflect the physiological state of their donor cells, they are also intensely surveyed as biomarker sources.
Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates Shu Liu, André Hossinger, Sarah Göbbels & Ina M. Vorberg? Journal Prion Volume 11, Issue 2 Pages 98-112 http://dx.doi.org/10.1080/19336896.2017.1306162

Complex complexity.Dionisio_{April 21, 2017
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Extracellular vesicles (EVs) are actively secreted, membrane-bound communication vehicles that exchange biomolecules between cells. EVs also serve as dissemination vehicles for pathogens, including prions, proteinaceous infectious agents that cause transmissible spongiform encephalopathies (TSEs) in mammals. Our knowledge of how protein aggregates are sorted into EVs and how these vesicles adhere to and fuse with target cells is limited.
Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates Shu Liu, André Hossinger, Sarah Göbbels & Ina M. Vorberg? Journal Prion Volume 11, Issue 2 Pages 98-112 http://dx.doi.org/10.1080/19336896.2017.1306162

Complex complexity.Dionisio_{April 21, 2017
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These studies have also provided a considerable surprise. Whether resection remains defective in all these RING-less models remains to be seen [...] Definitive evidence for or against cancer protection denoted by BRCA1-BARD1 Ub ligase activity awaits further investigation.
The BRCA1 Ubiquitin ligase function sets a new trend for remodelling in DNA repair Ruth M. Densham & Joanna R. Morris Journal Nucleus Volume 8, Issue 2 Pages 116-125 http://dx.doi.org/10.1080/19491034.2016.1267092

[#3223 addendum] Did somebody say "surprise"? Work in progress... stay tuned. Complex complexity.Dionisio_{April 21, 2017
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Proline is an amino acid with a unique cyclic structure that facilitates the folding of many proteins, but also impedes the rate of peptide bond formation by the ribosome. As a ribosome substrate, proline reacts markedly slower when compared with other amino acids both as a donor and as an acceptor of the nascent peptide. Furthermore, synthesis of peptides with consecutive proline residues triggers ribosome stalling. Here, we report crystal structures of the eukaryotic ribosome bound to analogs of mono- and diprolyl-tRNAs. These structures provide a high-resolution insight into unique properties of proline as a ribosome substrate. They show that the cyclic structure of proline residue prevents proline positioning in the amino acid binding pocket and affects the nascent peptide chain position in the ribosomal peptide exit tunnel. These observations extend current knowledge of the protein synthesis mechanism. They also revise an old dogma that amino acids bind the ribosomal active site in a uniform way by showing that proline has a binding mode distinct from other amino acids.
Molecular insights into protein synthesis with proline residues. Melnikov S, Mailliot J, Rigger L, Neuner S, Shin BS, Yusupova G, Dever TE, Micura R, Yusupov M EMBO Rep. 17(12):1776-1784. DOI: 10.15252/embr.201642943

Did somebody say "observations extend current knowledge"? Did somebody say "revise an old dogma"? Complex complexity.Dionisio_{April 21, 2017
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Biocontainment comprises any strategy applied to ensure that harmful organisms are confined to controlled laboratory conditions and not allowed to escape into the environment. Genetically engineered microorganisms (GEMs), regardless of the nature of the modification and how it was established, have potential human or ecological impact if accidentally leaked or voluntarily released into a natural setting. Although all evidence to date is that GEMs are unable to compete in the environment, the power of synthetic biology to rewrite life requires a pre-emptive strategy to tackle possible unknown risks. Physical containment barriers have proven effective but a number of strategies have been developed to further strengthen biocontainment. Research on complex genetic circuits, lethal genes, alternative nucleic acids, genome recoding and synthetic auxotrophies aim to design more effective routes towards biocontainment.
Synthetic biology approaches to biological containment: pre-emptively tackling potential risks. Torres L, Krüger A, Csibra E, Gianni E, Pinheiro VB Essays Biochem. 60(4):393-410. DOI: 10.1042/EBC20160013

Complex complexity.Dionisio_{April 21, 2017
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Genetic code expansion and reprogramming enable the site-specific incorporation of diverse designer amino acids into proteins produced in cells and animals.
Expanding and reprogramming the genetic code of cells and animals. Chin JW Annu Rev Biochem. 83:379-408. doi: 10.1146/annurev-biochem-060713-035737.

Did somebody say "reprogramming"? Did somebody say "designer"? Complex complexity.Dionisio_{April 21, 2017
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Orthogonal protein translation with noncanonical amino acids (ncAAs) has become a standard method in biosciences. Whereas much effort is made to broaden the chemical space of ncAAs, only few attempts on their systematic low-cost in situ production are reported until now. The main aim is to engineer cells with newly designed biosynthetic pathways coupled with orthogonal aminoacyl-tRNA synthetase/tRNA pairs (o-pairs). These should provide cost-effective solutions to industrially relevant bio-production problems, such as peptide/protein production beyond the canonical set of natural molecules and to expand the arsenal of chemistries available for living cells. Therefore, coupling genetic code expansion (GCE) with metabolic engineering is the basic prerequisite to transform orthogonal translation from a standard technique in academic research to industrial biotechnology.
Coupling genetic code expansion and metabolic engineering for synthetic cells. Völler JS, Budisa N Curr Opin Biotechnol. 48:1-7. doi: 10.1016/j.copbio.2017.02.002

Complex complexity.Dionisio_{April 21, 2017
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Genetic code expansion (GCE) has become a central topic of synthetic biology. GCE relies on engineered aminoacyl-tRNA synthetases (aaRSs) and a cognate tRNA species to allow codon reassignment by co-translational insertion of non-canonical amino acids (ncAAs) into proteins. Introduction of such amino acids increases the chemical diversity of recombinant proteins endowing them with novel properties. Such proteins serve in sophisticated biochemical and biophysical studies both in vitro and in vivo, they may become unique biomaterials or therapeutic agents, and they afford metabolic dependence of genetically modified organisms for biocontainment purposes.
Pyrrolysyl-tRNA synthetase, an aminoacyl-tRNA synthetase for genetic code expansion. Crnkovi? A, Suzuki T, Söll D, Reynolds NM Croat Chem Acta. 89(2):163-174. doi: 10.5562/cca2825

Complex complexity.Dionisio_{April 21, 2017
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Phosphorylation of many aminoacyl tRNA synthetases (AARSs) has been recognized for decades, but the contribution of post-translational modification to their primary role in tRNA charging and decryption of genetic code remains unclear. In contrast, phosphorylation is essential for performance of diverse noncanonical functions of AARSs unrelated to protein synthesis. Phosphorylation of glutamyl-prolyl tRNA synthetase (EPRS) has been investigated extensively in our laboratory for more than a decade, and has served as an archetype for studies of other AARSs. EPRS is a constituent of the IFN-?-activated inhibitor of translation (GAIT) complex that directs transcript-selective translational control in myeloid cells. Stimulus-dependent phosphorylation of EPRS is essential for its release from the parental multi-aminoacyl tRNA synthetase complex (MSC), for binding to other GAIT complex proteins, and for regulating the binding to target mRNAs. Importantly, phosphorylation is the common driving force for the context- and stimulus-dependent release, and non-canonical activity, of other AARSs residing in the MSC, for example, lysyl tRNA synthetase (KARS).
Experimental approaches for investigation of aminoacyl tRNA synthetase phosphorylation. Arif A, Jia J, Halawani D, Fox PL Methods. 113:72-82. doi: 10.1016/j.ymeth.2016.10.004

Complex complexity.Dionisio_{April 20, 2017
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[...] understanding the function of aminoacyl-tRNA synthetases appeared to be a task much more complicated than previously anticipated due to the numerous secondary, noncanonical functions that are performed by this family of enzymes. Association and dissociation of the components of the MARS seems to be an important checkpoint for many cellular pathways. The recent finding that splice-variant synthetases may fulfill functions independently of their primary role in translation, also unexpectedly expands the sphere of influence of this family of enzymes [...]
Aminoacyl-tRNA Synthetase Complexes in Evolution Svitlana Havrylenko and Marc Mirande Int J Mol Sci. 16(3): 6571–6594. doi: 10.3390/ijms16036571

Did somebody say "unexpectedly"? Work in progress... stay tuned. Complex complexity.Dionisio_{April 20, 2017
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The knowledge of the protein interfaces involved in the different facets of their activity is of fundamental importance [...] [...] an intricate interaction network makes it more difficult to design molecules capable of inhibiting a single pathway. It is not known whether the same surface area of LysRS is involved in the interaction with p38 and with all these secondary partners. It remains to be established whether association of LysRS with the native, full-length scaffold protein will reveal a similar interaction pattern.
Aminoacyl-tRNA Synthetase Complexes in Evolution Svitlana Havrylenko and Marc Mirande Int J Mol Sci. 16(3): 6571–6594. doi: 10.3390/ijms16036571

Work in progress... stay tuned. Complex complexity.Dionisio_{April 20, 2017
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Decoding of genetic information is an essential step for all living organisms. The process of translation of the genetic message contained in mRNA into proteins is a universal mechanism conserved, with minor modifications, in the three branches of the tree of life, from bacteria, archaea, and to eukaryotes. A family of enzymes, the aminoacyl-tRNA synthetases, is responsible for pairing a specific amino acid to a cognate tRNA, thus establishing a univocal relationship between a triplet of nucleotides, the anticodon, and an elementary piece of proteins.
Aminoacyl-tRNA Synthetase Complexes in Evolution Svitlana Havrylenko and Marc Mirande Int J Mol Sci. 16(3): 6571–6594. doi: 10.3390/ijms16036571

Complex complexity.Dionisio_{April 20, 2017
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Aminoacyl-tRNA synthetases are essential enzymes for interpreting the genetic code. They are responsible for the proper pairing of codons on mRNA with amino acids. In addition to this canonical, translational function, they are also involved in the control of many cellular pathways essential for the maintenance of cellular homeostasis. Association of several of these enzymes within supramolecular assemblies is a key feature of organization of the translation apparatus in eukaryotes. It could be a means to control their oscillation between translational functions, when associated within a multi-aminoacyl-tRNA synthetase complex (MARS), and nontranslational functions, after dissociation from the MARS and association with other partners.
Aminoacyl-tRNA Synthetase Complexes in Evolution Svitlana Havrylenko and Marc Mirande Int J Mol Sci. 16(3): 6571–6594. doi: 10.3390/ijms16036571

Complex complexity.Dionisio_{April 20, 2017
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Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. They are a family of twenty enzymes, one for each amino acid. By coupling an amino acid to a specific RNA triplet, the anticodon, they are responsible for interpretation of the genetic code. In addition to this translational, canonical role, several aminoacyl-tRNA synthetases also fulfill nontranslational, moonlighting functions. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. Because the balance between their alternative functions rests on the assembly and disassembly of this supramolecular entity, it is essential to get precise insight into the structural organization of this complex. The high-resolution 3D-structure of the native particle, with a molecular weight of about 1.5 MDa, is not yet known. Low-resolution structures of the multi-aminoacyl-tRNA synthetase complex, as determined by cryo-EM or SAXS, have been reported. High-resolution data have been reported for individual enzymes of the complex, or for small subcomplexes. This review aims to present a critical view of our present knowledge of the aminoacyl-tRNA synthetase complex in 3D. These preliminary data shed some light on the mechanisms responsible for the balance between the translational and nontranslational functions of some of its components.
The Aminoacyl-tRNA Synthetase Complex. Mirande M Subcell Biochem. 83:505-522. doi: 10.1007/978-3-319-46503-6_18.

Complex complexity.Dionisio_{April 20, 2017
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Re this comment by Dionisio: "Recent advances in genetic engineering allow the creation of synthetic organisms that incorporate noncanonical, or even unnatural, amino acids into the proteome." The infamous tryptophan food supplement disaster of 1989 demonstrated that the inaccurate unpredictably GMO technology can introduce new, toxic, "unnatural amino acids" into the human organism. The GE technology is still inaccurate and unpredictable in 2017. The GMO technology has virtually zero longterm safety studies. Lots of good data by independent scientsts, rather than the official junk data created by corporate-funded scientists, shows serious risks. Politics is the real dominant factor behind the GE technology. Not real science. One of the earliest GMO cases (a public experiment) that has preambled the long history of ignoring and suppressing the real dangers of GMO foods was the tryptophan supplement disaster of 1989 where the FDA ignored the warnings of their own scientists about the real risks of GMOs, simply to protect the business interests of the GMO industry, which they've been colluding with for decades - see http://www.supplements-and-health.com/l-tryptophan.html The government-biotech industrial complex has the average person believing that they're protecting their health. Yet, lying about real facts, denying real facts, or minimizing or ignoring real facts is not protecting or helping the public, it's deceiving the public.Jiy Jay_{April 20, 2017
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Aminoacylation reaction is the first step of protein biosynthesis. The catalytic reorganization at the active site of aminoacyl tRNA synthetases (aaRSs) is driven by the loop motions. There remain lacunae of understanding concerning the catalytic loop dynamics in aaRSs. We analyzed the functional loop dynamics in seryl tRNA synthetase from Methanopyrus kandleri (mkSerRS) and histidyl tRNA synthetases from Thermus thermophilus (ttHisRS), respectively, using molecular dynamics. Results confirm that the motif 2 loop and other active site loops are flexible spots within the catalytic domain. Catalytic residues of the loops form a network of interaction with the substrates to form a reactive state. The loops undergo transitions between closed state and open state and the relaxation of the constituent residues occurs in femtosecond to nanosecond time scale. Order parameters are higher for constituent catalytic residues which form a specific network of interaction with the substrates to form a reactive state compared to the Gly residues within the loop. The development of interaction is supported from mutation studies where the catalytic domain with mutated loop exhibits unfavorable binding energy with the substrates. During the open-close motion of the loops, the catalytic residues make relaxation by ultrafast librational motion as well as fast diffusive motion and subsequently relax rather slowly via slower diffusive motion. The Gly residues act as a hinge to facilitate the loop closing and opening by their faster relaxation behavior. The role of bound water is analyzed by comparing implicit solvent-based and explicit solvent-based simulations. Loops fail to form catalytically competent geometry in absence of water. The present result, for the first time reveals the nature of the active site loop dynamics in aaRS and their influence on catalysis.
Dynamics of the active site loops in catalyzing aminoacylation reaction in seryl and histidyl tRNA synthetases. Dutta S, Kundu S, Saha A, Nandi N J Biomol Struct Dyn. 1-15. doi: 10.1080/07391102.2017.1301272.

Complex complexity.Dionisio_{April 19, 2017
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A full exploration of the possibilities enabled by genetic code engineering requires an understanding of the key molecular biological and biochemical mechanisms underlying the modifications.
Efforts and Challenges in Engineering the Genetic Code. Lin X, Yu AC, Chan TF Life (Basel). 7(1). pii: E12. doi: 10.3390/life7010012.

Complex complexity.Dionisio_{April 19, 2017
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This year marks the 48th anniversary of Francis Crick's seminal work on the origin of the genetic code, in which he first proposed the "frozen accident" hypothesis to describe evolutionary selection against changes to the genetic code that cause devastating global proteome modification. However, numerous efforts have demonstrated the viability of both natural and artificial genetic code variations. Recent advances in genetic engineering allow the creation of synthetic organisms that incorporate noncanonical, or even unnatural, amino acids into the proteome. Currently, successful genetic code engineering is mainly achieved by creating orthogonal aminoacyl-tRNA/synthetase pairs to repurpose stop and rare codons or to induce quadruplet codons. In this review, we summarize the current progress in genetic code engineering and discuss the challenges, current understanding, and future perspectives regarding genetic code modification.
Efforts and Challenges in Engineering the Genetic Code. Lin X, Yu AC, Chan TF Life (Basel). 7(1). pii: E12. doi: 10.3390/life7010012.

Complex complexity.Dionisio_{April 19, 2017
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Aminoacyl tRNA synthetase-interacting multifunctional protein 1 (AIMP1) has been reported to have antitumor effects in various tumor models. However, mechanisms by which AIMP1 ameliorates tumorigenesis are not well understood. As NK cells are a major cell type involved in antitumor activities and AIMP1 is known to activate professional APCs, we determined whether AIMP1 induced NK cell activation directly or via these APCs. AIMP1 induced the expression of surface activation markers on murine NK cells in total splenocytes, although AIMP1 did not directly induce these activation markers of NK cells. The inductive effect of AIMP1 on NK cell activation disappeared in macrophage-depleted splenocytes, indicating that macrophages were required for the AIMP1-induced activation of NK cells. Furthermore, coculture experiments showed that AIMP1 activated NK cells in the presence of isolated macrophages, but failed to activate NK cells when cultured alone or with dendritic cells or B cells. Although AIMP1 significantly promoted TNF-? production by macrophages, the secreted TNF-? partially affected the NK cell activation. Transwell cocultivation analysis revealed that direct contact between macrophages and NK cells was required for the AIMP1-induced NK cell activation. In addition, AIMP1 significantly enhanced cytotoxicity of NK cells against Yac-1 cells. Furthermore, the in vivo administration of AIMP1 also induced NK cell activation systemically with a macrophage-dependent manner. Importantly, AIMP1 dramatically reduced the lung metastasis of melanoma cells, which was mediated by NK cells. Taken together, our results show that AIMP1 induces antitumor responses by NK cell activation mainly via macrophages.
Aminoacyl tRNA Synthetase--Interacting Multifunctional Protein 1 Activates NK Cells via Macrophages In Vitro and In Vivo. Kim MS, Song JH, Cohen EP, Cho D, Kim TS J Immunol. pii: 1601558. doi: 10.4049/jimmunol.1601558

Complex complexity.Dionisio_{April 19, 2017
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[...] the complexity of recombinant AMP expression including a functional PTM machinery and SPI/SCS-based ncAA incorporation (cf. Figure ?Figure11) presents a challenging task for bioprocess and production strain engineering. [...] AMP production could benefit from well-balanced expression and activity levels of precursor and PTM machinery genes. [...] combination of PTM enzymes from different AMPs offers additional diversity for the generation of novel AMPs [...]
Prospects of In vivo Incorporation of Non-canonical Amino Acids for the Chemical Diversification of Antimicrobial Peptides. Baumann T1, Nickling JH1, Bartholomae M2, Buivydas A2, Kuipers OP2, Budisa N1 Front Microbiol. 8:124. doi: 10.3389/fmicb.2017.00124.

Reprogrammable biological devices? Complex complexity.Dionisio_{April 19, 2017
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The incorporation of non-canonical amino acids (ncAA) is an elegant way for the chemical diversification of recombinantly produced antimicrobial peptides (AMPs). Residue- and site-specific installation methods in several bacterial production hosts hold great promise for the generation of new-to-nature AMPs, and can contribute to tackle the ongoing emergence of antibiotic resistance in pathogens. Especially from a pharmacological point of view, desirable improvements span pH and protease resistance, solubility, oral availability and circulation half-life.
Prospects of In vivo Incorporation of Non-canonical Amino Acids for the Chemical Diversification of Antimicrobial Peptides. Baumann T1, Nickling JH1, Bartholomae M2, Buivydas A2, Kuipers OP2, Budisa N1 Front Microbiol. 8:124. doi: 10.3389/fmicb.2017.00124.

Reprogrammable biological cells? Complex complexity.Dionisio_{April 19, 2017
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Genetic code engineering that enables reassignment of genetic codons to non-canonical amino acids (ncAAs) is a powerful strategy for enhancing ribosomally synthesized peptides and proteins with functions not commonly found in Nature. Reprogrammed cells or proteins equipped with synthetic structures are currently usually considered as useful tools for academic research or small applications. However, this engineering can even have practical importance when applications such as bioremediation (in open systems) biocatalysts or peptide-based drugs (closed systems) are considered50. For future bioengineering purposes, our system and its improved versions will doubtlessly provide a manifold of opportunities to design various novel ribosomally synthesized compounds.
Towards Biocontained Cell Factories: An Evolutionarily Adapted Escherichia coli Strain Produces a New-to-nature Bioactive Lantibiotic Containing Thienopyrrole-Alanine. Kuthning A1, Durkin P2, Oehm S2, Hoesl MG2, Budisa N2, Süssmuth RD Sci Rep. 6:33447. doi: 10.1038/srep33447.

Did somebody say "Reprogrammed"? Did somebody say "engineering"? Did somebody say "design"? Complex complexity.Dionisio_{April 19, 2017
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We present here, to our knowledge, the first example of Arg analog incorporation into membrane-bound receptors, and as such, these results describe an incisive approach to dissecting chemical interactions in a broad and therapeutically relevant family of membrane proteins. Interestingly, an H-bond network adjacent to the ligand binding site has been proposed for the structurally related glycine receptor (32), suggesting that stabilization of ligand binding by such H-bond networks could be a conserved feature of ligand recognition by pLGICs.
Unique Contributions of an Arginine Side Chain to Ligand Recognition in a Glutamate-gated Chloride Channel. Lynagh T, Komnatnyy VV, Pless SA J Biol Chem. 292(9):3940-3946. doi: 10.1074/jbc.M116.772939.

Complex complexity.Dionisio_{April 19, 2017
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Neurotransmitter receptors are vital signaling proteins that are embedded in the cell membrane and trigger intracellular changes in response to extracellular chemical signals. The two classical receptor types are metabotropic, G-protein-coupled receptors (GPCRs) that act over seconds or minutes via intracellular second messengers (1), and ionotropic, ligand-gated ion channels (LGICs)2 that mediate ion flux across the membrane on the millisecond timescale (2). The rapid chemo-electric signaling of LGICs is perfectly suited to the nervous system, where activation of sodium channels and chloride channels mediates excitatory and inhibitory signals, respectively (2). The first step in the process of activation is the recognition of a specific ligand, which in the case of the animal nervous system is very often the neurotransmitter glutamate (3).
Unique Contributions of an Arginine Side Chain to Ligand Recognition in a Glutamate-gated Chloride Channel. Lynagh T, Komnatnyy VV, Pless SA J Biol Chem. 292(9):3940-3946. doi: 10.1074/jbc.M116.772939.

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Glutamate recognition by neurotransmitter receptors often relies on Arg residues in the binding site, leading to the assumption that charge-charge interactions underlie ligand recognition. However, assessing the precise chemical contribution of Arg side chains to protein function and pharmacology has proven to be exceedingly difficult in such large and complex proteins. [...] Arg contributes crucially to ligand sensitivity via a hydrogen bond network, where Arg interacts both with agonist and with a conserved Thr side chain within the receptor. Together, the data provide a new explanation for the reliance of neurotransmitter receptors on Arg side chains and highlight the exceptional capacity of unnatural amino acid incorporation for increasing our understanding of ligand recognition.
Unique Contributions of an Arginine Side Chain to Ligand Recognition in a Glutamate-gated Chloride Channel. Lynagh T, Komnatnyy VV, Pless SA J Biol Chem. 292(9):3940-3946. doi: 10.1074/jbc.M116.772939.

Complex complexity.Dionisio_{April 19, 2017
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Error @3230: A large portion of the text got repeated by mistake.Dionisio_{April 19, 2017
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