Molecular Mechanism of “Charge Block-driven” Liquid-liquid Phase Separation and its Regulation by Phosphorylation

Abstract

Phosphorylation regulates protein function by altering stereospecific interaction with its substrate or partner proteins. However, recent studies demonstrated that phosphorylation preferably occurs in intrinsically disordered regions (IDRs), which do not have three-dimensional structures. Here, we describe how phosphorylation occurred in IDRs regulates the protein function. Mitotic phosphorylation in the IDRs of Ki-67 and NPM1 promotes or suppresses the liquid-liquid phase separation, respectively, by altering the “charge blockiness” along the polypeptide chain. The phosphorylation-mediated regulation of liquid-liquid phase separation by enhancing or suppressing “charge blockiness”, rather than by modulating stereospecific interaction, provides a new mechanism of protein regulation by post-translational modifications.