Using computational tools to take a closer look at stress granule proteins
Degenerative disorders like Alzheimer’s and Huntington’s are thought to be linked to protein misfolding and aggregation. Researchers are looking closely at protein aggregation mechanisms to gain more knowledge on how they work and how they are connected to neurodegenerative diseases. One particularly interesting group of proteins are those that form biological assemblies known as stress granules. Stress granules are large clusters of proteins and RNA that appear when cells are under stress or are exposed to harsh conditions, like high heat or during starvation. These granules help cells survive through tough times and may play a vital role in identifying key players in degenerative protein disorders.
In a paper published in the Journal of Molecular Biology, UBC Michael Smith Laboratories researchers compiled and analyzed recent data on stress granule proteins to determine shared characteristics of these biomolecules. Using this information, they have built computer models to determine which proteins are more likely to assemble within stress granules.
“While stress granules help cells survive harsh treatment, if the stress happens for too long or happens too frequently then these assemblies can get stuck together in a way that is hard for the cell to manage. Without proper regulation, protein misfolding and aggregation can happen which could lead to disease,” says Dr. Erich Kuechler, first author of the paper and a Postdoctoral Fellow in the laboratories of Dr. Thibault Mayor and Dr. Jörg Gsponer. “That’s why it is important to analyze stress granule proteins as they could potentially give us deeper insight into what drives the very beginning of these degenerative diseases.”
In the paper, Dr. Kuechler examines recent data detailing stress granule composition for both yeast and mammalian cells and extracts their defining protein characteristics. Computational analyses were then used to determine which characteristics best differentiate stress granule proteins from other proteins in the cell. Next, the researchers developed a computer model that assigned scores to the analyzed proteins that related to their likelihood of assembling within stress granules. Interestingly, though the researchers developed the program for stress granules, it was also very good at predicting other phase separating proteins. For example, a high-scoring protein would likely phase separate in a test tube or in other membraneless organelles.
A key finding from this paper showed that stress granule proteins are enriched for properties that favor a process known as protein liquid-liquid phase separation, a recently discovered phenomenon where proteins gather into more concentrated droplets within the cell. However, since this field is still very new and continues to be debated, more research is needed.
“This is a really exciting field and this paper could provide a resource for researchers looking to potentially find novel stress granule or phase separating proteins,” shares Dr. Kuechler.
This research is part of a collaboration that includes members from the laboratories of Dr. Thibault Mayor and Jörg Gsponer. Funding for this research is provided by the Canadian Institute of Health Research, NSERC, and the Michael Smith Foundation for Health Research.