Molecular Evolution of Cellular Condensates

University Of Utah, Salt Lake City UT

Investigators

Abstract

Living cells are composed of numerous molecular machines called proteins. Many proteins adopt structures dedicated to the cellular activities they carry out, and, as expected, these structures tend to persist over long evolutionary times. Recently, biologists started to appreciate that some proteins adopt much more flexible conformations that allow them to function by clustering with similar proteins. This project seeks to understand how this way of organizing the cell and regulating complex functions affects the rules governing how proteins that constitute such clusters change through evolution. In conjunction with the research goals of this project, the investigator will be developing a teaching curriculum using molecular animation and distributing these materials to cell biology instructors to help train the next generation of researchers. It has been traditionally believed that all cellular organelles are confined within a membrane. However, in recent years, membrane-less organelles, or condensates, are a newly appreciated way to organize the cell. The formation and functions of condensates are regulated by interactions more dynamic and labile than that of more commonly studied proteins, impacting how condensate constituents evolve. This project systematically analyzes condensate constituents in the model organism Caenorhabditis elegans to shed light on the molecular grammar of condensate members and on the forces shaping condensate evolution. The evolutionary patterns and rules uncovered by the phylogenetic analysis are then validated by mutating and swapping conserved domains and testing the functional impact of these changes. Beyond insight into the functions and evolution of condensates, this work charts a blueprint for future refinements of homology search algorithms resulting in improved gene annotations, sequence alignments and ortholog identification. The experimental work on this project is complemented by the creation of a teaching curriculum about condensates, including dedicated animations suited to represent dynamic interactions underlying the formation and functions and condensates. Distributing these materials to cell biology instructors will help train the next generation of researchers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.