Contrary to earlier assumptions, and could be clue to serious disease:
Newly identified mechanism solves enduring mystery of key element of cellular organization
The study focused on usually short-lived compartments called stress granules that form in cells under stress. Stress granules are just one type of the membrane-less structures or organelles that assemble as needed to handle various cell functions and then rapidly disperse. Until now, however, the mechanism underlying stress granule formation was poorly understood.
Stress granules are also tied to degenerative disorders such as ALS, which is also known as Lou Gehrig’s disease. Genes encoding the protein components of stress granules are often mutated in patients with ALS and other diseases. These same proteins accumulate in thread-like deposits called amyloid fibrils in the nerve and muscle cells of patients with ALS, frontotemporal dementia (FTD) and inclusion body myopathy (IBM). But the unifying mechanism was a mystery.
The disordered segment or “tail” of hnRNPA1, a protein that is sometimes mutated in ALS and related disorders, was the key to unlocking the connection among stress granules, fibrils and disease, said co-corresponding author Tanja Mittag, Ph.D., an assistant member of the St. Jude Department of Structural Biology. hnRNPA1 is an RNA-binding protein involved in stress granule formation.
In this study, researchers showed that under certain conditions related to temperature, salt and protein concentrations, hnRNPA1’s disordered tail prompts the protein to condense into liquid droplets through a process called liquid phase separation. The droplets have properties similar to stress granules, including the ability to fuse and grow.
Liquid phase separation is at work in a wide range of settings, including when oil and vinegar separate in salad dressing. Until recently, however, the process was not believed to play a role in normal cell function. This study is the first to link liquid phase separation to stress granule assembly.
“It is amazing to find out that proteins like hnRNPA1 have appeared in nature to mediate liquid phase separation under normal physiological conditions,” Mittag said. “The long disordered tails in these proteins enable membrane-less compartmentalization in cells. In addition, liquid phase separation is probably important for a whole range of fundamental biological processes.” More.