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 that intrinsically disordered regions (IDRs) play in their paralogs. Without a folded structure to restrain them, IDRs mutate more diversely along with evolution. However, how the diversity of IDRs in a paralog family affects their functions is unexplored. 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-2’s, is compensated by its higher α-helical propensity to assist their assembly. Our work suggests that, no matter how diverse they become, IDRs could evolve different traits to a converged function, such as liquid-liquid phase separation.