Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins

Abstract

Biologically active but floppy proteins represent a new reality of modern protein science. These intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered and intrinsically disordered protein regions (IDPRs) constitute a noticeable part of any given proteome. Functionally, they complement ordered proteins, and their conformational flexibility and structural plasticity allow them to perform impossible tricks and be engaged in biological activities that are inaccessible to well folded proteins with their unique structures. The major goals of this minireview are to show that, despite their simplified amino acid sequences, IDPs/IDPRs are complex entities often resembling chaotic systems, are structurally and functionally heterogeneous, and can be considered an important part of the structure-function continuum. Furthermore, IDPs/IDPRs are everywhere, and are ubiquitously engaged in various interactions characterized by a wide spectrum of binding scenarios and an even wider spectrum of structural and functional outputs.Brief Introduction: Why Those Proteins Are Clouds and Why Those Clouds Are Dancing "Dancing protein clouds" is a joke from a time when the newly born field of protein intrinsic disorder was trying to find an appropriate term to describe biologically active proteins without unique structures. The need for a specific term was determined by the clear recognition that those structureless functional proteins were fundamentally different from the "normal" globular proteins that used information encoded in their amino acid sequences to fold into specific, aperiodic crystal-like structures needed for specific biological functions. Fig. 1 reflects these attempts by representing different terms used in literature to describe such "strange" or "abnormal" proteins and shows that the "dancing protein clouds" expression is formed by superimposing "dancing proteins" and "protein clouds" descriptors. Although the phrase "dancing protein clouds" sounds like a parody, the term actually has deep meanings. The presence of a unique structure in a given protein means that when one would look at the sample containing this protein, s/he would find that all protein molecules are alike, that the structure of an individual molecule barely changes over time, and that the ensemble-averaged (or time-averaged) structure is identical, or at least very similar, to the structures of all individual protein molecules in that sample. In other words, if one would overlay all those individual structures, a crisp and clear image would be generated, similar to those found in the Protein Data Bank (PDB), and this ensemble-averaged structure would not change much over time. On the other hand, the lack of a unique structure in a given protein would create a highly dynamic ensemble, members of which would possess very different structures at any given moment, and the structure of any given molecule would change dramatically over time (therefore the "dancing protein" analogy). If one would try to overlay all those structures,...

Paradoxes and wonders of intrinsic disorder: Stability of instability

“…These structure-forming potential of elevated temperatures was attributed to the peculiarities of the amino acid compositions of the extended IDPs (namely, their overall low level of hydrophobicity) leading to their "turned out" response to heating: higher temperatures caused the increase in strength of the hydrophobic interaction, leading to a stronger hydrophobic attraction, which is the major driving force for protein folding. 48,49,102 Similar "turned out" response to changes in pH was reported for several extended IDPs, such as prothymosin a, 78 a-synuclein, 102 pig calpastatin domain I, 106 histidine rich protein II, 107 naturally occurring human peptide LL-37, 108 and several other extended IDPs. Here, partial folding of extended IDPs (which are characterized by the high net charge at neutral pH) in solutions with extremely high or low pH values can be attributed to the minimization of the overall net charge, thereby decreasing charge-charge intramolecular repulsion and permitting hydrophobic-driven collapse to the partially-folded conformation.…”

“…[68][69][70][71][72][73][74][75][76][77] High resilience of intrinsic disorder Although lacking stable structure, possessing noncooperative unfolding behavior, and showing high sensitivity to proteolysis, one of the most intriguing biophysical properties ascribed to highly disordered proteins is their extraordinary resilience, where an IDP can sustain exposure to the extremely harsh environmental conditions, being able either to keep its functionality under these extreme conditions or to rapidly regain it after returning to normal conditions. 48,49 An illustrative example of such behavior is given by a "funny protein" prothymosin a, 48 which triggered my interest to the intrinsically disordered proteins by its unusual ability to be unharmed by the prolonged exposure to harsh conditions (activity of the protein was not affected by boiling for a few days).…”

“…31,47 Many aspects related to the structure, conformational behavior and functionality of IDPs look rather strange from the viewpoint of "traditional" ordered proteins. 48,49 To give a brief outlook of various paradoxes and wonders of intrinsic disorder, a series of short comments on different unusual features of IDPs was started in the Intrinsically Disordered Proteins journal. The first comment in this series was dedicated to the introduction of the "prevalence of exceptionality" paradox, where a progression was shown in understanding of the natural abundance of IDPs from the early days, when they were taken as rare exceptions, to the current days, when the prevalence of IDPs/IDPRs in various proteomes and biological processes is well accepted.…”

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

“…These compartments are formed through phase-separation of RNAbinding proteins that contain low-complexity sequence domains (LCDs) Hyman et al, 2014;Mateju et al, 2017). These proteins are intrinsically disordered, which makes them impossible to crystalize Uversky, 2016). They can promiscuously interact with multiple proteins Kroschwald et al, 2015), which complicates defining their biological functions, and how they are regulated such that they are included in different RNPs upon reversible stress is poorly understood in vivo.…”

Intrinsic disorder in spondins and some of their interacting partners

“…However, with recent advances in protein science, it has been proven that some genes in the eukaryotic genomes encode entire proteins or large segments of proteins that lack a well-structured 3-dimensional fold. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] These intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) have important biological roles and are crucial for many cellular processes, such as signaling, transcriptional and translational activities. 3,4,8,[10][11][12][15][16][17][18][19][20] Some IDPRs function as linkers between ordered domains, many of them frequently serve as sites of posttranslational modifications, or as regions affected by disease-related mutations, gene truncations or translocations.…”