Disorder in Protein Switches

Abstract

Interactions of intrinsically disordered (ID) protein segments with partner proteins are often mediated by molecular recognition features (MoRFs). MoRFs in ID segments are not only used in interactions in trans but also in cis, i.e., they can mediate interactions between an ID segment and a domain that are both part of the same polypeptide chain. Such interactions in cis can switch the function of a protein domain off by steric or allosteric inhibition of substrate or binding partner access to catalytic sites or binding surfaces, respectively. This phenomenon is called autoinhibition. We demonstrate that most cis‐regulatory elements in proteins are ID and that the MoRFs in these ID autoinhibitory regions are highly conserved. We present results from molecular dynamics simulations that reveal the mechanism by which phosphorylation of MoRFs can relieve autoinhibition and introduce the first predictor that identifies ID autoinhibitory regions in proteins from sequence information only.