Functional unfoldomics: Roles of intrinsic disorder in protein (multi)functionality

Abstract

Intrinsically disordered proteins (IDPs), which are functional proteins without stable tertiary structure, and hybrid proteins containing ordered domains and intrinsically disordered regions (IDRs) constitute prominent parts of all proteomes collectively known as unfoldomes. IDPs/IDRs exist as highly dynamic structural ensembles of rapidly interconverting conformations and are characterized by the exceptional structural heterogeneity, where their different parts are (dis)ordered to different degree, and their overall structure represents a complex mosaic of foldons, inducible foldons, inducible morphing foldons, non-foldons, semifoldons, and even unfoldons. Despite their lack of unique 3D structures, IDPs/IDRs play crucial roles in the control of various biological processes and the regulation of different cellular pathways and are commonly involved in recognition and signaling, indicating that the disorder-based functional repertoire is complementary to the functions of ordered proteins. Furthermore, IDPs/IDRs are frequently multifunctional, and this multifunctionality is defined by their structural flexibility and heterogeneity. Intrinsic disorder phenomenon is at the roots of the structure-function continuum model, where the structure continuum is defined by the presence of differently (dis)ordered regions, and the function continuum arises from the ability of all these differently (dis)ordered parts to have different functions. In their everyday life, IDPs/IDRs utilize a broad spectrum of interaction mechanisms thereby acting as interaction specialists. They are crucial for the biogenesis of numerous proteinaceous membrane-less organelles driven by the liquid-liquid phase separation. This review introduces functional unfoldomics by representing some aspects of the intrinsic disorder-based functionality.

Keywords: Intrinsically disordered proteins; Intrinsically disordered regions; Liquid-liquid phase separation; Membrane-less organelles; Molecular recognition; Posttranslational modifications; Protein function; Protein-protein interactions.