Longstanding collaboration leads to new findings about processes associated with neurodegenerative diseases.
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.
Image credit: Acagastya via Wikimedia
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 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.”