Expanding the Paradigm: Intrinsically Disordered Proteins and Allosteric Regulation

Abstract

Allosteric regulatory processes are implicated at all levels of biological function. Recent advances in our understanding of the diverse and functionally significant class of intrinsically disordered proteins have identified a multitude of ways in which disordered proteins function within the confines of the allosteric paradigm. Allostery within or mediated by intrinsically disordered proteins ensures robust and efficient signal integration through mechanisms that would be extremely unfavorable or even impossible for globular protein interaction partners. Here, we highlight recent examples that indicate the breadth of biological outcomes that can be achieved through allosteric regulation by intrinsically disordered proteins. Ongoing and future work in this rapidly evolving area of research will expand our appreciation of the central role of intrinsically disordered proteins in ensuring the fidelity and efficiency of cellular regulation.

Hydrogen exchange of chemoreceptors in functional complexes suggests protein stabilization mediates long-range allosteric coupling

“…Interestingly, in the related sensor histidine kinases (which contain the sensor and kinase within the same protein), signalingrelated local unfolding of helices has been observed by HDX-MS (33,34). Additional study of the role of folding/stabilization in chemoreceptor signaling is important to provide a detailed understanding of the mechanism and how it compares to observations in other systems in which more localized folding/unfolding is key to signaling mechanisms (35), and in cases where intrinsically disordered domains mediate allosteric interactions (36).…”

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

“…In a comprehensive bioinformatics study carried out by Xie et al, a positive correlation between the functional annotation of the SwissProt database and the predicted intrinsic disorder has been found. Generally, IDPs/IDRs are enriched in proteins involved in signaling and regulatory functions, including transcription regulation, cell cycle, mRNA processing, scaffolding, and apoptosis . Consequently, dysregulation of IDPs/IDRs are associated with a variety of human diseases .…”

“…Most recently, many IDPs/IDRs are found to be able to undergo liquid–liquid phase separation (LLPS), which is related to the assembling of membraneless organelles in vivo . So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence–structure–function relationship of proteins . Recently, the protein structure–function continuum concept was proposed by Uversky to illustrate the numerous biological functions of p53 through multiple proteoforms by various mechanisms and may be extended to many multi‐function IDPs …”

“…Generally, IDPs/IDRs are enriched in proteins involved in signaling and regulatory functions, including transcription regulation, cell cycle, mRNA processing, scaffolding, and apoptosis. 6,14,15,[18][19][20][21][22][23][24][25][26][27][28][29][30][31] Consequently, dysregulation of IDPs/IDRs are associated with a variety of human diseases. [32][33][34][35][36][37][38][39][40][41][42][43][44] Most recently, many IDPs/IDRs are found to be able to undergo liquid-liquid phase separation (LLPS), which is related to the assembling of membraneless organelles in vivo.…”

“…[45][46][47][48][49][50][51][52][53] So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence-structurefunction relationship of proteins. 29,[54][55][56] Recently, the protein structure-function continuum concept was proposed by Uversky to illustrate the numerous biological functions of p53 through multiple proteoforms by various mechanisms and may be extended to many multi-function IDPs. 57 In this review, we will summarize recent advances of our understanding on the molecular recognition of IDPs/IDRs.…”