Phase separation driven by interchangeable properties in the intrinsically disordered regions of protein paralogs

Abstract

Paralogs, arising from gene duplications, increase the functional diversity of proteins. Protein functions in paralog families have been extensively studied, but little is known about the roles of intrinsically disordered regions (IDRs), even though more than half of eukaryotic proteins have them. Using the RNA-binding protein Musashi family as an example, we applied multiple structural techniques and phylogenetic analysis to show how members in a paralog family have evolved their IDRs to different physicochemical properties but converge to the same function. In this example, the lower prion-like tendency of Musashi-1's IDRs, rather than Musashi-2s', is compensated by its higher α-helical propensity to assist their assembly. Without a folded structure to restraint, IDRs' sequences mutate faster along with evolution. No matter how fast they change, our work suggests that IDRs evolve different traits to a converged function, such as liquid-liquid phase separation.