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• W2897029606 abstract "Articles assembled to this Special Issue use the perspective of protein intrinsic disorder to highlight different aspects of the dark proteome (i.e., a part of protein universe that includes proteins, which are not amenable to experimental structure determination by existing means and inaccessible to homology modeling) and some of its components. They illustrate that IDPs/IDPRs do not only serve as important constituents of the biological dark matter, but clearly act as the dark horse of the protein universe, being almost completely unknown or at least very little known in a recent past, but suddenly emerging to prominence. About two decades ago, when I started working on α-synuclein, a seditious idea of the possible commonness of structure-less proteins with important biological functions struck my mind. It was kind of a revelation. However, to be completely honest, this revelation should have happened a few years earlier. In fact, α-synuclein represented already a third case of natively unfolded proteins I personally dealt with, with two other highly disordered but functional proteins being prothymosin α1 and phosphodiesterase γ subunit.2 Then, there were several personally witnessed cases of “broken” proteins, which did not have unique 3-structure as a result of the removal of natural ligands (e.g., α-fetoprotein3 or many other globular proteins4) or due to some mutations (e.g., mutated5 or circularly permuted dihydrofolate reductase6). But, of course, these cases of “broken” proteins do not count, since all of them were shown to fold in the presence of natural ligands or substrates and therefore could be classified as underfolded globular proteins. Somehow, despite repeatedly seeing functional disorder over and over again, mind tempered by training within the frames of a classical structure–function paradigm failed to accept an idea that the functionality of a coil-like “funny” protein with obscure amino acid sequence7 could be much more than a unique exception, and that the lack of a unique structure in a functional protein could be much more than a reflection of the fact that this protein is brocken or underfolded. How many “rare” exceptions from an accepted rule one should see to recognize that a new rule is needed? Personal experience shows that this number is three. The probability of having three “rare” exceptions in one pair of hands is really low, thus a new rule should be thought of to explain the existence of disorder-based functionality.8 Curiosuly, at the turn of the century, the related ideas that not all protein functions require well-formed structures, and that many biologically active proteins can be disordered were proposed independently and almost simultaneously by several research groups.8-10 The original numbers of what is known now as experimentally validated intrinsically disordered proteins (IDPs) were rather modest, but over the years, the list experienced continuous and steady growth starting from 6111 and expanding to 91,8 150,12 157,13 200+,10, 14 and culminating in 800+ nonredundant IDPs assembled in the DisProt database.15 This represents the “prevalence of exceptionality” paradox related to the commonness of the protein intrinsic disorder phenomenon.16 Eventually, it resulted in the recognition that IDPs consititute a very significant part of the protein universe prevailing in various proteomes and biological processes. The validity of this idea is supported now by numerous computational studies on the disorder penetrance at the proteome level.17 The IDP containing, mostly unexplored, but very significant part of the protein universe was classified as “dark proteome”,18 since IDPs or intrinsically disordered protein regions (IDPRs) of hybrid proteins are not amenable to experimental structure determination by existing means and inaccessible to homology modeling, and since little is known about disorder-based mechanisms and functions. This first part of the Special Issue in Proteomics entitled “The Dark Proteome and Related Structural Proteomics” represents a set of 16 papers (four reviews, ten research articles, one viewpoint and one commentary) that use the perspective of protein intrinsic disorder to highlight different aspects of the dark proteome and some of its components. A research article by Schafferhans et al. checked the hypothesis that the darkest members of the dark human proteome (i.e., proteins for which there is no any structural information (experimental or predicted based on the homology-based models) for any part of the amino acid sequence) are less abundantly expressed than the non-dark proteins (in which at least part of the sequence has a known or inferred structure).19 The output of this study was completely unexpected, since the authors revealed that there is no difference in the expression levels of dark and non-dark proteins, indicating that dark proteins are massively produced at both mRNA and protein levels.19 This is at stark contrast to the results of the comprehensive analysis of the modern life science literature conducted by Sinha et al. in order to evaluate the level of biological function discovery.20 The authors showed that the overwhelming majority of the scientific literature is about less than 5000 “elite” genes, whereas thousands of human proteins have never been mentioned at all.20 Therefore, despite massive production of dark proteins,19 which is clearly a reflection of their biological importance, the function discovery rate remains very low for the big portion of human proteome20 that clearly continues to keep its functionality in darkness. To find a potential correlation between structural coverage, degree of putative intrinsic disorder, and predicted propensity for structure determination at th proteome level, Hu et al. conducted a comprehensive analysis of 5.4 million proteins from 987 proteomes in the three domains of life and viruses.21 This analysis revealed that at the proteome level, the darkness is rooted in the presence of significantly elevated amounts of intrinsic disorder and in the prevalence of proteins that are predicted to be difficult to solve structurally.21 According to Harrison,22 the abundant presence of compositionally biased regions that have a low probability of being structural domains or intrinsically disordered regions can constitute another reason for proteome darkness. Several papers included to this Special Issue considered some specific functional features of large groups of intrinsically disordered proteins. For example, Chowdhury et al. utilized two modern complementary sequence-based methods to decipher some of the aspects pertaining to the landscape of protein-RNA interactions in the human proteome.23 Using this approach, the authors identified 1500+ RNA-binding proteins, many of which were novel and were significantly under-annotated functionally.23 Janis et al. presented a comprehensive review of the various molecular strategies, which different anhydrobiotic invertebrates are using in order to survive extreme water stress and clearly showed that a central role in the desiccation tolerance in all species investigated is played by anhydrobiosis-related intrinsically disordered (ARID) proteins.24 ARID proteins are characterized by very different sequence characteristics and can be grouped into two classes, proteins functioining in hydrated state and proteins gaining functionality during desiccation.24 Based on the comprehensive in vitro analysis, Meyers et al. revealed that although the substrates of the 20S proteasome core particle (20S CP) are highly disordered (i.e., they constitute 20S-IDPome), not all IDPs can serve as the 20S CP substrates.25 Among characteristic features of the members of 20S-IDPome are binding promiscuity, abundance of posttranslational modification sites, capability for RNA binding, and ability to undergo liquid–liquid phase transitions leading to the formation of proteinaceous membrane-less organelles (PMLOs), thereby suggesting crucial role of 20S CP in PMLO biogenesis.25 Basavanhally et al. used intrinsic disorder to look at three proteins (SLITRK5, SLITRK6, and TSHR), specific single nucleotide polymorphisms (SNPs) in which were shown to be associated with male homosexuality,26 whereas Olson conducted an adaptive temperature-based replica exchange simulation to get better understanding of the molecular mechanisms underlying the conformational selection of a polyproline peptide by ebola virus VP30.27 Three papers looked at the different aspects of one of the best studied IDPs, α-synuclein, a presynaptic neuronal protein that is linked to the pathogenesis of Parkinson's disease (PD) and other neurodegenerative diseases known as synucleinopathies. Limatola et al. reported utilization of the time-resolved NMR spectroscopy to study site-specific cleavage of α-synuclein by various endopeptidases under neutral and low pH conditions in vitro, as well as by endogenous cellular proteases in extracts of unchallenged and challenged cells in response to Rotenone-induced oxidative stress.28 This study showed that although α-synuclein is characterized by the exceptional proteolytic stability under physiological cellular conditions, induction of cell stress enhanced the protease susceptibility of this protein.28 Using an important observation that in several ailments, many neuronal IDPs can co-aggregate with α-synuclein, Bhasne and Mukhopadhyay overviewed the role of heterotypic protein–protein interactions in the formation of heteroamyloids.29 In the same vein, Williams et al. provided a systematic overview of the roles of β-synuclein in regulation of α-synuclein and highlighted studies showing that many different stages of α-synuclein aggregation can be regulated by β-synuclein that interacts with α-synuclein at the monomer, oligomer, and surface levels.30 Two articles describe utilization of computational tools for the IDP analysis. Bitard-Feildel et al. illustrated how Hydrophobic Cluster Analysis (HCA), which is a useful originally designed for the analysis of sequences of foldable proteins, can be utilized to give insight into the IDPs and IDPRs.31 These authors showed how HCA can be used for finding short disorder-based binding sites that become ordered upon contact with partners, as well as for identifying large conditionally disordered domains, which are stabilized by interaction with partners.31 Jain et al. represented a pipeline for finding moonlighting proteins (i.e., proteins with two or more independent and distinct functions) from several different sources of information, such as database entries, large-scale Omics data, and literature, and used a literature-mining method, DextMP to find new moonlighting proteins in Arabidopsis thaliana, Caenorhabditis elegans, and Drosophila melanogaster proteomes.32 Finally, we present a viewpoint article, where we discuss the potential roles of IDPs and IDPRs in the origin of life, evolution of the first independent primordial living unit that preceded the Last Universal Common Ancestor (LUCA), some major evolutionary transitions, such as appearance of multicellularity, as well as their potential relation to the phenotypic switching and the emergence of new traits.33" @default.
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• W2897029606 title "Bringing Darkness to Light: Intrinsic Disorder as a Means to Dig into the Dark Proteome" @default.
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