Abstract
Regulation of protein binding through autoinhibition commonly occurs via interactions involving intrinsically disordered regions (IDRs). These intramolecular interactions can directly or allosterically inhibit intermolecular protein or DNA binding, regulate enzymatic activity, and control the assembly of large macromolecular complexes. Autoinhibitory interactions mediated by protein disorder are inherently transient, making their identification and characterization challenging. In this review, we explore the structural and functional diversity of disorder-mediated autoinhibition for a variety of biological mechanisms, with a focus on the role of multivalency and effective concentration. We also discuss the evolution of disordered motifs that participate in autoinhibition using examples where sequence conservation varies from high to low. In some cases, identifiable motifs that are essential for autoinhibition remain intact within a rapidly evolving sequence, over long evolutionary distances. Finally, we examine the potential of AlphaFold2 to predict autoinhibitory intramolecular interactions involving IDRs.