Polybivalency and disordered proteins in ordering macromolecular assemblies

Abstract

Intrinsically disordered proteins (IDPs) are prevalent in macromolecular assemblies and are thought to mediate protein recognition in complex regulatory processes and signaling pathways. The formation of a polybivalent scaffold is a key process by which IDPs drive early steps in macromolecular assemblies. Three intrinsically disordered proteins, IC, Swallow and Nup159, are core components, respectively, of cytoplasmic dynein, bicoid mRNA localization apparatus, and nuclear pore complexes. In all three systems, the hub protein LC8 recognizes on the IDP, short linear motifs that are fully disordered in the apo form, but adopt a β-strand when bound to LC8. The IDP/LC8 complex forms a bivalent scaffold primed to bind additional bivalent ligands. Scaffold formation also promotes self-association and/or higher order organization of the IDP components at a site distant from LC8 binding. Rigorous thermodynamic analyses imply that association of additional bivalent ligands is driven by entropic effects where the first binding event is weak but subsequent binding of additional ligands occurs with higher affinity. Here, we review specific examples of macromolecular assemblies in which polybivalency of aligned IDP duplexes not only enhances binding affinity and results in formation of a stable complex but also compensates unfavorable steric and enthalpic interactions. We propose that polybivalent scaffold assembly involving IDPs and LC8-like proteins is a general process in the cell biology of a class of multi-protein structures that are stable yet fine-tuned for diverse cellular requirements.

The multifaceted roles of intrinsic disorder in protein complexes

“…Multivalent interactions involving the linked associations of ligands binding to multiple sites on a receptor confer increased affinity compared to binding to monovalent receptors [74]. The idea of cooperative polyvalent binding has been successfully exploited during the development of the polyvalent inhibitors of anthrax toxin produced by the causative agent of anthrax, Bacillus anthracis [75,76].…”

“…Recently, an important role of bivalent and polybivalent scaffolds in assembly of protein complexes has been emphasized [74]. Here, two monovalent IDP chains are incorporated into a bivalent macromolecular scaffold, within which each disordered chain possesses one binding site.…”

“…Here, two monovalent IDP chains are incorporated into a bivalent macromolecular scaffold, within which each disordered chain possesses one binding site. The two IDP chains involved in the formation of such a bivalent scaffold are linked via binding to a dimeric protein with two symmetrical binding sites or by self-association [74]. Curiously, the formation of bivalent scaffolds might result in a duplex with multiple additional bivalent sites, creating a polybivalent scaffold, and promote subsequent self-association and/or higher order organization of the IDP components [74].…”

“…The two IDP chains involved in the formation of such a bivalent scaffold are linked via binding to a dimeric protein with two symmetrical binding sites or by self-association [74]. Curiously, the formation of bivalent scaffolds might result in a duplex with multiple additional bivalent sites, creating a polybivalent scaffold, and promote subsequent self-association and/or higher order organization of the IDP components [74]. The formation of a bivalent scaffolds are not necessarily accompanied by detectable changes in protein structure and dynamics [74].…”

“…Curiously, the formation of bivalent scaffolds might result in a duplex with multiple additional bivalent sites, creating a polybivalent scaffold, and promote subsequent self-association and/or higher order organization of the IDP components [74]. The formation of a bivalent scaffolds are not necessarily accompanied by detectable changes in protein structure and dynamics [74]. Illustrative examples of bivalent and polybivalent scaffolds include complexes between Swallow and LC8, Nup159 and LC8, and the dynein intermediate and light chains [74].…”