Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling

Abstract

Understanding signaling and other complex biological processes requires elucidating the critical roles of intrinsically disordered proteins and regions (IDPs/IDRs), which represent ~30% of the proteome and enable unique regulatory mechanisms. In this review we describe the structural heterogeneity of disordered proteins that underpins these mechanisms and the latest progress in obtaining structural descriptions of ensembles of disordered proteins that are needed for linking structure and dynamics to function. We describe the diverse interactions of IDPs that can have unusual characteristics such as “ultrasensitivity” and “regulated folding and unfolding”. We also summarize the mounting data showing that large-scale assembly and protein phase separation occurs within a variety of signaling complexes and cellular structures. In addition, we discuss efforts to therapeutically target disordered proteins with small molecules. Overall, we interpret the remodeling of disordered state ensembles due to binding and post-translational modifications within an expanded framework for allostery that provides significant insights into how disordered proteins transmit biological information.

The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

“…For instance, Q/N-rich regions are important for forming cellular assemblies, such as P-bodies, FG-rich regions are critical in forming the hydrogel-like structure of the nuclear pore, and repeats of multiple linear motifs can mediate phase separation and organize matter in cells, as seen in certain actin regulatory proteins (Figure 5) [92,99–102]. Thus, IDRs can mediate functions comparable to structured domains, such as (i) the formation of protein complexes and higher-order assemblies of variable stoichiometry of subunits [86], (ii) conformational transition (disorder-to-order and order-to-disorder) in response to specific environmental changes, context, or ligands [94], and (iii) allosteric communication [15,60,103–105]. Since most proteins contain structured and disordered regions in varying proportions, together with structured domains in the same polypeptide chain, IDRs can synergistically increase the functional versatility of proteins [12,15].…”

Finding Our Way in the Dark Proteome

“…IDPs/IDRs, which are estimated to make up approximately one-third of the human genome 1–4 , pose new challenges for the structure-function paradigm since they take advantage of their disordered state to interact with numerous partners for signaling, regulation and transcription 5–8 . At the same time disease-related proteins are highly enriched in IDRs, including those that are central to neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, prion diseases, and Alzheimer’s disease (AD), as well as cancer-associated proteins that have a primary function in regulatory protein interactions.…”

A Small Molecule Causes a Population Shift in the Conformational Landscape of an Intrinsically Disordered Protein

“…Intrinsically disordered proteins (IDPs) and disordered regions (IDRs) within proteins mediate myriad cellular functions 1 and underlie numerous human diseases. 1–3 While the functions of many are understood 1,3 , open questions remain regarding the dynamic features of IDPs and how they affect interactions with other macromolecules and small molecule ligands.…”

“…1–3 While the functions of many are understood 1,3 , open questions remain regarding the dynamic features of IDPs and how they affect interactions with other macromolecules and small molecule ligands. 4–6 IDPs are inherently flexible and are generally described as ensembles of disordered conformations.…”