Phase separation focus of collaborative research with St. Jude
Rohit Pappu’s lab uncovers hierarchy of interactions
Phase separation is a process cells use to sort and separate distinct protein and nucleic acid components. As a process, phase separation helps ensure regulation of cellular matter in space and time. Aberrant phase transitions lead to clumps of proteins inside cells, a hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.
Scientists at St. Jude Children’s Research Hospital in Memphis, Tenn., and Washington University in St. Louis are working together to study the rules underlying phase separation.
The labs of Tanja Mittag at St. Jude and Rohit Pappu, the Gene K. Beare Distinguished Professor of biomedical engineering at the McKelvey School of Engineering, created a stickers-and-spacers model to discern the rules underlying the driving forces for phase separation. The "stickers" and "spacers" are different types of amino acids along the protein chain.
The valence, or number, of stickers and the linear arrangement of stickers versus spacers has been shown by the Mittag and Pappu labs to have an impact on phase separation.
Building on that work, the Mittag and Pappu labs have uncovered a hierarchy of sticker and spacer interactions, gleaned using evolutionary analysis, and affirmed using biophysical measurements and physical theories. A new result to emerge is the role of net charge and the imbalance of charged amino acids on the driving forces for phase separation.
A paper on the work was published Dec. 20 in the journal Nature Chemistry.
“Our work showcases the hidden complexities inherent to low-complexity domains,” said co-corresponding author Pappu. “Hierarchies of interaction strengths are encoded at the sequence level and utilized to generate emergent behaviors such as phase separation."
Working with the Mittag lab, Mina Farag, an MD-PhD student in the Pappu lab, helped formulate and test a set of rules for evolutionarily conserved sequence fingerprints, gleaned using novel informatics and physics-based approaches, as determinants of phase behavior of low complexity domains. The findings have direct relevance for understanding how sequence mutations affect disease phenotypes in the context of ALS.
“We now have a concept that allows us to know what the stickers and spacers are doing in every sequence context, instead of having to study each individual sequence separately,” Mittag said.
Read the full article on the St. Jude website.
The study was funded by the National Institutes of Health (5R01NS056114, R01NS121114, P30GM138395); the Air Force Office of Scientific Research (FA9550-20-1-0241); the St. Jude Collaborative Research Consortium on Membranelles Organelles and Foundation; and ALSAC, the fundraising and awareness organization of St. Jude.