Shapeshifting proteins: the role of structural disorder and conformational plasticity in physiology and disease

The classical sequence–structure–function paradigm states that the amino acid sequence dictates the folding of a polypeptide chain into a unique, biologically active, functional protein molecule. While this is generally true for a large fraction of the proteome, intense research over the past few decades has revealed the unique biological role of structural disorder and conformational plasticity of proteins. Such shapeshifting proteins belong to the class of intrinsically disordered proteins/regions (IDPs/IDRs). Conformational plasticity in these protein molecules allows them to exist in a multitude of states capable of performing an array of functions. An emerging body of work over the past decade has revealed that some of these functions can also be achieved via the spatiotemporally regulated formation of membrane-less organelles or biomolecular condensates that are formed via liquid–liquid phase separation of proteins and nucleic acids. While such liquid-like intracellular compartments are associated with a range of cellular functions, they can also undergo an aberrant phase transition into gel-like/solid-like aggregates that are linked to several human diseases. Research efforts in this area are beginning to illuminate the critical role of structural disorder in a wide range of biological functions and deadly human diseases. This thematic issue on ‘Shapeshifting Proteins’ in Essays in Biochemistry includes timely accounts from some of the top-flight experts and captures the latest exciting discoveries in the field.

This issue has several important articles that address the broad aspect of structural disorder and phase behavior of IDPs/IDRs studied using a diverse array of computational and experimental tools. The piece by Fuxreiter outlines new findings on multiple modes of interactions and cellular context dependence of proteins involved in biological interactions and assemblies [1]. Fonin et al. provided an outline of biomolecular condensates derived from IDPs [2]. Shakhnovich and co-workers described various structural and viscoelastic roots of aberrant phase transitions of IDPs [3]. Forman-Kay demonstrated the power of nuclear magnetic resonance (NMR) spectroscopy in characterizing dynamic complexes and phase-separated condensates of IDPs [4]. Soranno and co-workers described the single-molecule biophysics perspective of IDPs [5]. Wu, Perrett, and co-workers demonstrated the utility of single-molecule fluorescence in studying IDPs in phase-separated condensed phase [6]. Kragelund and co-workers stated how phosphorylation modulates the conformational ensemble of IDPs and their functions [7]. Three interesting articles in this thematic issue dealt with the role of intrinsic disorder in viral proteins. Gondelaud et al. outlined the functional benefit of disorder for the replication of measles, Nipah, and Hendra viruses [8]. Ivarsson and co-workers described the role of short linear motifs (SLiMs) and long disordered domains in mediating interactions between viral proteins and host proteins [9]. Chemes and co-workers narrated the role of SLiMs in the evolution of viral hijack functions [10]. Several important articles in this thematic issue dealt with phase separation and aggregation of IDPs that are associated with a range of human pathologies, including neurodegenerative diseases, metabolic diseases, cancers, and systemic amyloidosis. Radford and co-workers described the current approaches used in the search for small-molecule modulators of amyloid fibril formation [11]. Wittung-Stafshede described the intriguing effects of copper ions in α-synuclein amyloid formation that is linked to Parkinson’s disease [12]. Maji and co-workers narrated the current development in a range of α-synuclein self-assembles including oligomers, amyloids, and phase-separated condensates that are associated with Parkinson’s disease [13]. Serpell and co-workers summarized the recent development in the self-assembly of tau into paired helical and straight filaments and other assembly states that are associated with Alzheimer’s disease and other tauopathies [14]. Chakraborty and Zweckstetter described the emerging aspects of the phase behavior of tau [15]. Silva and co-workers addressed the issue of aberrant phase separation and amyloid aggregation of p53 linked to cancer [16]. Interestingly, in addition to disease-associate amyloids, there are amyloids, termed functional amyloids, that are involved in a range of functions from bacteria to humans. Otzen’s article narrated the molecular process involved in the bacterial functional amyloidogenesis that occurs via a carefully orchestrated sequence of events [17].

All the articles in this thematic issue on ‘Shapeshifting Proteins’ capture the current trends and growing excitement in the rapidly evolving field of IDPs. I thank all authors for their outstanding contributions to this exciting issue. I am thankful to the editorial staff of Essays in Biochemistry for their help. I am also grateful to the anonymous reviewers who reviewed and provided their valuable comments and suggestions on the articles published in this issue. I hope this thematic issue will be of great interest to all the researchers in protein science as well as beyond the boundary of the field.

The author declares that there are no competing interests associated with the manuscript.

IDP

intrinsically disordered protein

IDR

intrinsically disordered region

SLiM

short linear motif