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1
Han, Bingqing, Chongjiao Ren, Wenda Wang, Jiashan Li, and Xinqi Gong. "Computational Prediction of Protein Intrinsically Disordered Region Related Interactions and Functions." Genes 14, no. 2 (February 8, 2023): 432. http://dx.doi.org/10.3390/genes14020432.
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Intrinsically Disordered Proteins (IDPs) and Regions (IDRs) exist widely. Although without well-defined structures, they participate in many important biological processes. In addition, they are also widely related to human diseases and have become potential targets in drug discovery. However, there is a big gap between the experimental annotations related to IDPs/IDRs and their actual number. In recent decades, the computational methods related to IDPs/IDRs have been developed vigorously, including predicting IDPs/IDRs, the binding modes of IDPs/IDRs, the binding sites of IDPs/IDRs, and the molecular functions of IDPs/IDRs according to different tasks. In view of the correlation between these predictors, we have reviewed these prediction methods uniformly for the first time, summarized their computational methods and predictive performance, and discussed some problems and perspectives.
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Coskuner-Weber, Orkid, and Vladimir N. Uversky. "Current Stage and Future Perspectives for Homology Modeling, Molecular Dynamics Simulations, Machine Learning with Molecular Dynamics, and Quantum Computing for Intrinsically Disordered Proteins and Proteins with Intrinsically Disordered Regions." Current Protein & Peptide Science 25, no. 2 (February 2024): 163–71. http://dx.doi.org/10.2174/0113892037281184231123111223.
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Abstract:: The structural ensembles of intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered regions (IDRs) cannot be easily characterized using conventional experimental techniques. Computational techniques complement experiments and provide useful insights into the structural ensembles of IDPs and proteins with IDRs. Herein, we discuss computational techniques such as homology modeling, molecular dynamics simulations, machine learning with molecular dynamics, and quantum computing that can be applied to the studies of IDPs and hybrid proteins with IDRs. We also provide useful future perspectives for computational techniques that can be applied to IDPs and hybrid proteins containing ordered domains and IDRs.
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Liu, Meili, Akshaya K. Das, James Lincoff, Sukanya Sasmal, Sara Y. Cheng, Robert M. Vernon, Julie D. Forman-Kay, and Teresa Head-Gordon. "Configurational Entropy of Folded Proteins and Its Importance for Intrinsically Disordered Proteins." International Journal of Molecular Sciences 22, no. 7 (March 26, 2021): 3420. http://dx.doi.org/10.3390/ijms22073420.
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Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve the description of IDPs/IDRs but are largely in disagreement with solution experiments for the disordered states. This work considers a new direction—the connection to configurational entropy—and how it might change the nature of our understanding of protein force field development to equally well encompass globular proteins, IDRs/IDPs, and disorder-to-order transitions. We have evaluated representative pairwise and many-body protein and water force fields against experimental data on representative IDPs and IDRs, a peptide that undergoes a disorder-to-order transition, for seven globular proteins ranging in size from 130 to 266 amino acids. We find that force fields with the largest statistical fluctuations consistent with the radius of gyration and universal Lindemann values for folded states simultaneously better describe IDPs and IDRs and disorder-to-order transitions. Hence, the crux of what a force field should exhibit to well describe IDRs/IDPs is not just the balance between protein and water energetics but the balance between energetic effects and configurational entropy of folded states of globular proteins.
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Felli, Isabella C., Wolfgang Bermel, and Roberta Pierattelli. "Exclusively heteronuclear NMR experiments for the investigation of intrinsically disordered proteins: focusing on proline residues." Magnetic Resonance 2, no. 1 (July 1, 2021): 511–22. http://dx.doi.org/10.5194/mr-2-511-2021.
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Abstract. NMR represents a key spectroscopic technique that contributes to the emerging field of highly flexible, intrinsically disordered proteins (IDPs) or protein regions (IDRs) that lack a stable three-dimensional structure. A set of exclusively heteronuclear NMR experiments tailored for proline residues, highly abundant in IDPs/IDRs, are presented here. They provide a valuable complement to the widely used approach based on amide proton detection, filling the gap introduced by the lack of amide protons in proline residues within polypeptide chains. The novel experiments have very interesting properties for the investigations of IDPs/IDRs of increasing complexity.
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Ahmed, Shehab S., Zaara T. Rifat, Ruchi Lohia, Arthur J. Campbell, A. Keith Dunker, M. Sohel Rahman, and Sumaiya Iqbal. "Characterization of intrinsically disordered regions in proteins informed by human genetic diversity." PLOS Computational Biology 18, no. 3 (March 11, 2022): e1009911. http://dx.doi.org/10.1371/journal.pcbi.1009911.
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All proteomes contain both proteins and polypeptide segments that don’t form a defined three-dimensional structure yet are biologically active—called intrinsically disordered proteins and regions (IDPs and IDRs). Most of these IDPs/IDRs lack useful functional annotation limiting our understanding of their importance for organism fitness. Here we characterized IDRs using protein sequence annotations of functional sites and regions available in the UniProt knowledgebase (“UniProt features”: active site, ligand-binding pocket, regions mediating protein-protein interactions, etc.). By measuring the statistical enrichment of twenty-five UniProt features in 981 IDRs of 561 human proteins, we identified eight features that are commonly located in IDRs. We then collected the genetic variant data from the general population and patient-based databases and evaluated the prevalence of population and pathogenic variations in IDPs/IDRs. We observed that some IDRs tolerate 2 to 12-times more single amino acid-substituting missense mutations than synonymous changes in the general population. However, we also found that 37% of all germline pathogenic mutations are located in disordered regions of 96 proteins. Based on the observed-to-expected frequency of mutations, we categorized 34 IDRs in 20 proteins (DDX3X, KIT, RB1, etc.) as intolerant to mutation. Finally, using statistical analysis and a machine learning approach, we demonstrate that mutation-intolerant IDRs carry a distinct signature of functional features. Our study presents a novel approach to assign functional importance to IDRs by leveraging the wealth of available genetic data, which will aid in a deeper understating of the role of IDRs in biological processes and disease mechanisms.
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Alshehri, Manal A., Manee M. Manee, Mohamed B. Al-Fageeh, and Badr M. Al-Shomrani. "Genomic Analysis of Intrinsically Disordered Proteins in the Genus Camelus." International Journal of Molecular Sciences 21, no. 11 (June 3, 2020): 4010. http://dx.doi.org/10.3390/ijms21114010.
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Intrinsically disordered proteins/regions (IDPs/IDRs) fail to fold completely into 3D structures, but have major roles in determining protein function. While natively disordered proteins/regions have been found to fulfill a wide variety of primary cellular roles, the functions of many disordered proteins in numerous species remain to be uncovered. Here, we perform the first large-scale study of IDPs/IDRs in the genus Camelus, one of the most important mammalians in Asia and North Africa, in order to explore the biological roles of these proteins. The study includes the prediction of disordered proteins/regions in Camelus species and in humans using multiple state-of-the-art prediction tools. Additionally, we provide a comparative analysis of Camelus and Homo sapiens IDPs/IDRs for the sake of highlighting the distinctive use of disorder in each genus. Our findings indicate that the human proteome is more disordered than the Camelus proteome. Gene Ontology analysis also revealed that Camelus IDPs are enriched in glutathione catabolism and lactose biosynthesis.
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Medvedev, Kirill E., Jimin Pei, and Nick V. Grishin. "DisEnrich: database of enriched regions in human dark proteome." Bioinformatics 38, no. 7 (January 30, 2022): 1870–76. http://dx.doi.org/10.1093/bioinformatics/btac051.
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Abstract Motivation Intrinsically disordered proteins (IDPs) are involved in numerous processes crucial for living organisms. Bias in amino acid composition of these proteins determines their unique biophysical and functional features. Distinct intrinsically disordered regions (IDRs) with compositional bias play different important roles in various biological processes. IDRs enriched in particular amino acids in human proteome have not been described consistently. Results We developed DisEnrich—the database of human proteome IDRs that are significantly enriched in particular amino acids. Each human protein is described using Gene Ontology (GO) function terms, disorder prediction for the full-length sequence using three methods, enriched IDR composition and ranks of human proteins with similar enriched IDRs. Distribution analysis of enriched IDRs among broad functional categories revealed significant overrepresentation of R- and Y-enriched IDRs in metabolic and enzymatic activities and F-enriched IDRs in transport. About 75% of functional categories contain IDPs with IDRs significantly enriched in hydrophobic residues that are important for protein–protein interactions. Availability and implementation The database is available at http://prodata.swmed.edu/DisEnrichDB/. Supplementary information Supplementary data are available at Bioinformatics Advances online.
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Kastano, Kristina, Gábor Erdős, Pablo Mier, Gregorio Alanis-Lobato, Vasilis J. Promponas, Zsuzsanna Dosztányi, and Miguel A. Andrade-Navarro. "Evolutionary Study of Disorder in Protein Sequences." Biomolecules 10, no. 10 (October 6, 2020): 1413. http://dx.doi.org/10.3390/biom10101413.
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Intrinsically disordered proteins (IDPs) contain regions lacking intrinsic globular structure (intrinsically disordered regions, IDRs). IDPs are present across the tree of life, with great variability of IDR type and frequency even between closely related taxa. To investigate the function of IDRs, we evaluated and compared the distribution of disorder content in 10,695 reference proteomes, confirming its high variability and finding certain correlation along the Euteleostomi (bony vertebrates) lineage to number of cell types. We used the comparison of orthologs to study the function of disorder related to increase in cell types, observing that multiple interacting subunits of protein complexes might gain IDRs in evolution, thus stressing the function of IDRs in modulating protein-protein interactions, particularly in the cell nucleus. Interestingly, the conservation of local compositional biases of IDPs follows residue-type specific patterns, with E- and K-rich regions being evolutionarily stable and Q- and A-rich regions being more dynamic. We provide a framework for targeted evolutionary studies of the emergence of IDRs. We believe that, given the large variability of IDR distributions in different species, studies using this evolutionary perspective are required.
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McFadden, William M., and Judith L. Yanowitz. "idpr: A package for profiling and analyzing Intrinsically Disordered Proteins in R." PLOS ONE 17, no. 4 (April 18, 2022): e0266929. http://dx.doi.org/10.1371/journal.pone.0266929.
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Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are proteins or protein-domains that do not have a single native structure, rather, they are a class of flexible peptides that can rapidly adopt multiple conformations. IDPs are quite abundant, and their dynamic characteristics provide unique advantages for various biological processes. The field of “unstructured biology” has emerged, in part, because of numerous computational studies that had identified the unique characteristics of IDPs and IDRs. The package ‘idpr’, short for Intrinsically Disordered Proteins in R, implements several R functions that match the established characteristics of IDPs to protein sequences of interest. This includes calculations of residue composition, charge-hydropathy relationships, and predictions of intrinsic disorder. Additionally, idpr integrates several amino acid substitution matrices and calculators to supplement IDP-based workflows. Overall, idpr aims to integrate tools for the computational analysis of IDPs within R, facilitating the analysis of these important, yet under-characterized, proteins. The idpr package can be downloaded from Bioconductor (https://bioconductor.org/packages/idpr/).
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Saito, Akatsuki, Maya Shofa, Hirotaka Ode, Maho Yumiya, Junki Hirano, Toru Okamoto, and Shige H. Yoshimura. "How Do Flaviviruses Hijack Host Cell Functions by Phase Separation?" Viruses 13, no. 8 (July 28, 2021): 1479. http://dx.doi.org/10.3390/v13081479.
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Viral proteins interact with different sets of host cell components throughout the viral life cycle and are known to localize to the intracellular membraneless organelles (MLOs) of the host cell, where formation/dissolution is regulated by phase separation of intrinsically disordered proteins and regions (IDPs/IDRs). Viral proteins are rich in IDRs, implying that viruses utilize IDRs to regulate phase separation of the host cell organelles and augment replication by commandeering the functions of the organelles and/or sneaking into the organelles to evade the host immune response. This review aims to integrate current knowledge of the structural properties and intracellular localizations of viral IDPs to understand viral strategies in the host cell. First, the properties of viral IDRs are reviewed and similarities and differences with those of eukaryotes are described. The higher IDR content in viruses with smaller genomes suggests that IDRs are essential characteristics of viral proteins. Then, the interactions of the IDRs of flaviviruses with the MLOs of the host cell are investigated with emphasis on the viral proteins localized in the nucleoli and stress granules. Finally, the possible roles of viral IDRs in regulation of the phase separation of organelles and future possibilities for antiviral drug development are discussed.
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Gill, Michelle L., R. Andrew Byrd, and Arthur G. Palmer, III. "Dynamics of GCN4 facilitate DNA interaction: a model-free analysis of an intrinsically disordered region." Physical Chemistry Chemical Physics 18, no. 8 (2016): 5839–49. http://dx.doi.org/10.1039/c5cp06197k.
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Brocca, Stefania, Rita Grandori, Sonia Longhi, and Vladimir Uversky. "Liquid–Liquid Phase Separation by Intrinsically Disordered Protein Regions of Viruses: Roles in Viral Life Cycle and Control of Virus–Host Interactions." International Journal of Molecular Sciences 21, no. 23 (November 28, 2020): 9045. http://dx.doi.org/10.3390/ijms21239045.
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Intrinsically disordered proteins (IDPs) are unable to adopt a unique 3D structure under physiological conditions and thus exist as highly dynamic conformational ensembles. IDPs are ubiquitous and widely spread in the protein realm. In the last decade, compelling experimental evidence has been gathered, pointing to the ability of IDPs and intrinsically disordered regions (IDRs) to undergo liquid–liquid phase separation (LLPS), a phenomenon driving the formation of membrane-less organelles (MLOs). These biological condensates play a critical role in the spatio-temporal organization of the cell, where they exert a multitude of key biological functions, ranging from transcriptional regulation and silencing to control of signal transduction networks. After introducing IDPs and LLPS, we herein survey available data on LLPS by IDPs/IDRs of viral origin and discuss their functional implications. We distinguish LLPS associated with viral replication and trafficking of viral components, from the LLPS-mediated interference of viruses with host cell functions. We discuss emerging evidence on the ability of plant virus proteins to interfere with the regulation of MLOs of the host and propose that bacteriophages can interfere with bacterial LLPS, as well. We conclude by discussing how LLPS could be targeted to treat phase separation-associated diseases, including viral infections.
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Vovk, Andrei, and Anton Zilman. "Effects of Sequence Composition, Patterning and Hydrodynamics on the Conformation and Dynamics of Intrinsically Disordered Proteins." International Journal of Molecular Sciences 24, no. 2 (January 11, 2023): 1444. http://dx.doi.org/10.3390/ijms24021444.
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Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) perform diverse functions in cellular organization, transport and signaling. Unlike the well-defined structures of the classical natively folded proteins, IDPs and IDRs dynamically span large conformational and structural ensembles. This dynamic disorder impedes the study of the relationship between the amino acid sequences of the IDPs and their spatial structures and dynamics, with different experimental techniques often offering seemingly contradictory results. Although experimental and theoretical evidence indicates that some IDP properties can be understood based on their average biophysical properties and amino acid composition, other aspects of IDP function are dictated by the specifics of the amino acid sequence. We investigate the effects of several key variables on the dimensions and the dynamics of IDPs using coarse-grained polymer models. We focus on the sequence “patchiness” informed by the sequence and biophysical properties of different classes of IDPs—and in particular FG nucleoporins of the nuclear pore complex (NPC). We show that the sequence composition and patterning are well reflected in the global conformational variables such as the radius of gyration and hydrodynamic radius, while the end-to-end distance and dynamics are highly sequence-specific. We find that in good solvent conditions highly heterogeneous sequences of IDPs can be well mapped onto averaged minimal polymer models for the purpose of prediction of the IDPs dimensions and dynamic relaxation times. The coarse-grained simulations are in a good agreement with the results of atomistic MD. We discuss the implications of these results for the interpretation of the recent experimental measurements, and for the further applications of mesoscopic models of FG nucleoporins and IDPs more broadly.
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Fujiwara, Satoru. "Dynamical Behavior of Disordered Regions in Disease-Related Proteins Revealed by Quasielastic Neutron Scattering." Medicina 58, no. 6 (June 13, 2022): 795. http://dx.doi.org/10.3390/medicina58060795.
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Background and Objectives: Intrinsically disordered proteins (IDPs) and proteins containing intrinsically disordered regions (IDRs) are known to be involved in various human diseases. Since the IDPs/IDRs are fluctuating between many structural substrates, the dynamical behavior of the disease-related IDPs/IDRs needs to be characterized to elucidate the mechanisms of the pathogenesis of the diseases. As protein motions have a hierarchy ranging from local side-chain motions, through segmental motions of loops or disordered regions, to diffusive motions of entire molecules, segmental motions, as well as local motions, need to be characterized. Materials and Methods: Combined analysis of quasielastic neutron scattering (QENS) spectra with the structural data provides information on both the segmental motions and the local motions of the IDPs/IDRs. Here, this method is applied to re-analyze the QENS spectra of the troponin core domain (Tn-CD), various mutants of which cause the pathogenesis of familial cardiomyopathy (FCM), and α-synuclein (αSyn), amyloid fibril formation of which is closely related to the pathogenesis of Parkinson’s disease, collected in the previous studies. The dynamical behavior of wild-type Tn-CD, FCM-related mutant Tn-CD, and αSyn in the different propensity states for fibril formation is characterized. Results: In the Tn-CD, the behavior of the segmental motions is shown to be different between the wild type and the mutant. This difference is likely to arise from changes in the intramolecular interactions, which are suggested to be related to the functional aberration of the mutant Tn-CD. In αSyn, concerted enhancement of the segmental motions and the local motions is observed with an increased propensity for fibril formation, suggesting the importance of these motions in fibril formation. Conclusions: Characterization of the segmental motions as well as the local motions is thus useful for discussing how the changes in dynamical behavior caused by the disease-related mutations and/or environmental changes could be related to the functional and/or behavioral aberrations of these proteins.
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Chiang, Wan-Chin, Ming-Hsuan Lee, Tsai-Chen Chen, and Jie-rong Huang. "Interactions between the Intrinsically Disordered Regions of hnRNP-A2 and TDP-43 Accelerate TDP-43′s Conformational Transition." International Journal of Molecular Sciences 21, no. 16 (August 18, 2020): 5930. http://dx.doi.org/10.3390/ijms21165930.
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Most biological functions involve protein–protein interactions. Our understanding of these interactions is based mainly on those of structured proteins, because encounters between intrinsically disordered proteins (IDPs) or proteins with intrinsically disordered regions (IDRs) are much less studied, regardless of the fact that more than half eukaryotic proteins contain IDRs. RNA-binding proteins (RBPs) are a large family whose members almost all have IDRs in addition to RNA binding domains. These IDRs, having low sequence similarity, interact, but structural details on these interactions are still lacking. Here, using the IDRs of two RBPs (hnRNA-A2 and TDP-43) as a model, we demonstrate that the rate at which TDP-43′s IDR undergoes the neurodegenerative disease related α-helix-to-β-sheet transition increases in relation to the amount of hnRNP-A2′s IDR that is present. There are more than 1500 RBPs in human cells and most of them have IDRs. RBPs often join the same complexes to regulate genes. In addition to the structured RNA-recognition motifs, our study demonstrates a general mechanism through which RBPs may regulate each other’s functions through their IDRs.
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Pintado-Grima, Carlos, Oriol Bárcenas, and Salvador Ventura. "In-Silico Analysis of pH-Dependent Liquid-Liquid Phase Separation in Intrinsically Disordered Proteins." Biomolecules 12, no. 7 (July 12, 2022): 974. http://dx.doi.org/10.3390/biom12070974.
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Intrinsically disordered proteins (IDPs) are essential players in the assembly of biomolecular condensates during liquid–liquid phase separation (LLPS). Disordered regions (IDRs) are significantly exposed to the solvent and, therefore, highly influenced by fluctuations in the microenvironment. Extrinsic factors, such as pH, modify the solubility and disorder state of IDPs, which in turn may impact the formation of liquid condensates. However, little attention has been paid to how the solution pH influences LLPS, despite knowing that this process is context-dependent. Here, we have conducted a large-scale in-silico analysis of pH-dependent solubility and disorder in IDRs known to be involved in LLPS (LLPS-DRs). We found that LLPS-DRs present maximum solubility around physiological pH, where LLPS often occurs, and identified significant differences in solubility and disorder between proteins that can phase-separate by themselves or those that require a partner. We also analyzed the effect of mutations in the resulting solubility profiles of LLPS-DRs and discussed how, as a general trend, LLPS-DRs display physicochemical properties that permit their LLPS at physiologically relevant pHs.
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Watson, Matthew, and Katherine Stott. "Disordered domains in chromatin-binding proteins." Essays in Biochemistry 63, no. 1 (April 2019): 147–56. http://dx.doi.org/10.1042/ebc20180068.
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Abstract Chromatin comprises proteins, DNA and RNA, and its function is to condense and package the genome in a way that allows the necessary transactions such as transcription, replication and repair to occur in a highly organised and regulated manner. The packaging of chromatin is often thought of in a hierarchical fashion starting from the most basic unit of DNA packaging, the nucleosome, to the condensation of nucleosomal ‘beads on a string’ by linker histones to form the 30-nm fibre and eventually large chromatin domains. However, a picture of a more heterogeneous, dynamic and liquid-like assembly is emerging, in which intrinsically disordered proteins (IDPs) and proteins containing intrinsically disordered regions (IDRs) play a central role. Disorder features at all levels of chromatin organisation, from the histone tails, which are sites of extensive post-translational modification (PTM) that change the fate of the underlying genomic information, right through to transcription hubs, and the recently elucidated roles of IDPs and IDRs in the condensation of large regions of the genome through liquid–liquid phase separation.
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Bianchi, Greta, Sonia Longhi, Rita Grandori, and Stefania Brocca. "Relevance of Electrostatic Charges in Compactness, Aggregation, and Phase Separation of Intrinsically Disordered Proteins." International Journal of Molecular Sciences 21, no. 17 (August 27, 2020): 6208. http://dx.doi.org/10.3390/ijms21176208.
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The abundance of intrinsic disorder in the protein realm and its role in a variety of physiological and pathological cellular events have strengthened the interest of the scientific community in understanding the structural and dynamical properties of intrinsically disordered proteins (IDPs) and regions (IDRs). Attempts at rationalizing the general principles underlying both conformational properties and transitions of IDPs/IDRs must consider the abundance of charged residues (Asp, Glu, Lys, and Arg) that typifies these proteins, rendering them assimilable to polyampholytes or polyelectrolytes. Their conformation strongly depends on both the charge density and distribution along the sequence (i.e., charge decoration) as highlighted by recent experimental and theoretical studies that have introduced novel descriptors. Published experimental data are revisited herein in the frame of this formalism, in a new and possibly unitary perspective. The physicochemical properties most directly affected by charge density and distribution are compaction and solubility, which can be described in a relatively simplified way by tools of polymer physics. Dissecting factors controlling such properties could contribute to better understanding complex biological phenomena, such as fibrillation and phase separation. Furthermore, this knowledge is expected to have enormous practical implications for the design, synthesis, and exploitation of bio-derived materials and the control of natural biological processes.
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Avramov, Miloš, Éva Schád, Ágnes Révész, Lilla Turiák, Iva Uzelac, Ágnes Tantos, László Drahos, and Željko D. Popović. "Identification of Intrinsically Disordered Proteins and Regions in a Non-Model Insect Species Ostrinia nubilalis (Hbn.)." Biomolecules 12, no. 4 (April 18, 2022): 592. http://dx.doi.org/10.3390/biom12040592.
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Research in previous decades has shown that intrinsically disordered proteins (IDPs) and regions in proteins (IDRs) are as ubiquitous as highly ordered proteins. Despite this, research on IDPs and IDRs still has many gaps left to fill. Here, we present an approach that combines wet lab methods with bioinformatics tools to identify and analyze intrinsically disordered proteins in a non-model insect species that is cold-hardy. Due to their known resilience to the effects of extreme temperatures, these proteins likely play important roles in this insect’s adaptive mechanisms to sub-zero temperatures. The approach involves IDP enrichment by sample heating and double-digestion of proteins, followed by peptide and protein identification. Next, proteins are bioinformatically analyzed for disorder content, presence of long disordered regions, amino acid composition, and processes they are involved in. Finally, IDP detection is validated with an in-house 2D PAGE. In total, 608 unique proteins were identified, with 39 being mostly disordered, 100 partially disordered, 95 nearly ordered, and 374 ordered. One-third contain at least one long disordered segment. Functional information was available for only 90 proteins with intrinsic disorders out of 312 characterized proteins. Around half of the 90 proteins are cytoskeletal elements or involved in translational processes.
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Pang, Yihe, and Bin Liu. "IDP-LM: Prediction of protein intrinsic disorder and disorder functions based on language models." PLOS Computational Biology 19, no. 11 (November 22, 2023): e1011657. http://dx.doi.org/10.1371/journal.pcbi.1011657.
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Intrinsically disordered proteins (IDPs) and regions (IDRs) are a class of functionally important proteins and regions that lack stable three-dimensional structures under the native physiologic conditions. They participate in critical biological processes and thus are associated with the pathogenesis of many severe human diseases. Identifying the IDPs/IDRs and their functions will be helpful for a comprehensive understanding of protein structures and functions, and inform studies of rational drug design. Over the past decades, the exponential growth in the number of proteins with sequence information has deepened the gap between uncharacterized and annotated disordered sequences. Protein language models have recently demonstrated their powerful abilities to capture complex structural and functional information from the enormous quantity of unlabelled protein sequences, providing opportunities to apply protein language models to uncover the intrinsic disorders and their biological properties from the amino acid sequences. In this study, we proposed a computational predictor called IDP-LM for predicting intrinsic disorder and disorder functions by leveraging the pre-trained protein language models. IDP-LM takes the embeddings extracted from three pre-trained protein language models as the exclusive inputs, including ProtBERT, ProtT5 and a disorder specific language model (IDP-BERT). The ablation analysis shown that the IDP-BERT provided fine-grained feature representations of disorder, and the combination of three language models is the key to the performance improvement of IDP-LM. The evaluation results on independent test datasets demonstrated that the IDP-LM provided high-quality prediction results for intrinsic disorder and four common disordered functions.
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Grahl, Matheus V. Coste, Fernanda Cortez Lopes, Anne H. Souza Martinelli, Celia R. Carlini, and Leonardo L. Fruttero. "Structure-Function Insights of Jaburetox and Soyuretox: Novel Intrinsically Disordered Polypeptides Derived from Plant Ureases." Molecules 25, no. 22 (November 16, 2020): 5338. http://dx.doi.org/10.3390/molecules25225338.
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Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) do not have a stable 3D structure but still have important biological activities. Jaburetox is a recombinant peptide derived from the jack bean (Canavalia ensiformis) urease and presents entomotoxic and antimicrobial actions. The structure of Jaburetox was elucidated using nuclear magnetic resonance which reveals it is an IDP with small amounts of secondary structure. Different approaches have demonstrated that Jaburetox acquires certain folding upon interaction with lipid membranes, a characteristic commonly found in other IDPs and usually important for their biological functions. Soyuretox, a recombinant peptide derived from the soybean (Glycine max) ubiquitous urease and homologous to Jaburetox, was also characterized for its biological activities and structural properties. Soyuretox is also an IDP, presenting more secondary structure in comparison with Jaburetox and similar entomotoxic and fungitoxic effects. Moreover, Soyuretox was found to be nontoxic to zebra fish, while Jaburetox was innocuous to mice and rats. This profile of toxicity affecting detrimental species without damaging mammals or the environment qualified them to be used in biotechnological applications. Both peptides were employed to develop transgenic crops and these plants were active against insects and nematodes, unveiling their immense potentiality for field applications.
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Davey, Norman E., M. Madan Babu, Martin Blackledge, Alan Bridge, Salvador Capella-Gutierrez, Zsuzsanna Dosztanyi, Rachel Drysdale, et al. "An intrinsically disordered proteins community for ELIXIR." F1000Research 8 (October 15, 2019): 1753. http://dx.doi.org/10.12688/f1000research.20136.1.
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Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are now recognised as major determinants in cellular regulation. This white paper presents a roadmap for future e-infrastructure developments in the field of IDP research within the ELIXIR framework. The goal of these developments is to drive the creation of high-quality tools and resources to support the identification, analysis and functional characterisation of IDPs. The roadmap is the result of a workshop titled “An intrinsically disordered protein user community proposal for ELIXIR” held at the University of Padua. The workshop, and further consultation with the members of the wider IDP community, identified the key priority areas for the roadmap including the development of standards for data annotation, storage and dissemination; integration of IDP data into the ELIXIR Core Data Resources; and the creation of benchmarking criteria for IDP-related software. Here, we discuss these areas of priority, how they can be implemented in cooperation with the ELIXIR platforms, and their connections to existing ELIXIR Communities and international consortia. The article provides a preliminary blueprint for an IDP Community in ELIXIR and is an appeal to identify and involve new stakeholders.
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Sammak, Susan, and Giovanna Zinzalla. "Targeting protein–protein interactions (PPIs) of transcription factors: Challenges of intrinsically disordered proteins (IDPs) and regions (IDRs)." Progress in Biophysics and Molecular Biology 119, no. 1 (October 2015): 41–46. http://dx.doi.org/10.1016/j.pbiomolbio.2015.06.004.
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Erdős, Gábor, Mátyás Pajkos, and Zsuzsanna Dosztányi. "IUPred3: prediction of protein disorder enhanced with unambiguous experimental annotation and visualization of evolutionary conservation." Nucleic Acids Research 49, W1 (May 28, 2021): W297—W303. http://dx.doi.org/10.1093/nar/gkab408.
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Abstract Intrinsically disordered proteins and protein regions (IDPs/IDRs) exist without a single well-defined conformation. They carry out important biological functions with multifaceted roles which is also reflected in their evolutionary behavior. Computational methods play important roles in the characterization of IDRs. One of the commonly used disorder prediction methods is IUPred, which relies on an energy estimation approach. The IUPred web server takes an amino acid sequence or a Uniprot ID/accession as an input and predicts the tendency for each amino acid to be in a disordered region with an option to also predict context-dependent disordered regions. In this new iteration of IUPred, we added multiple novel features to enhance the prediction capabilities of the server. First, learning from the latest evaluation of disorder prediction methods we introduced multiple new smoothing functions to the prediction that decreases noise and increases the performance of the predictions. We constructed a dataset consisting of experimentally verified ordered/disordered regions with unambiguous annotations which were added to the prediction. We also introduced a novel tool that enables the exploration of the evolutionary conservation of protein disorder coupled to sequence conservation in model organisms. The web server is freely available to users and accessible at https://iupred3.elte.hu.
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Sun, Xiaolin, William T. Jones, and Erik H. A. Rikkerink. "GRAS proteins: the versatile roles of intrinsically disordered proteins in plant signalling." Biochemical Journal 442, no. 1 (January 27, 2012): 1–12. http://dx.doi.org/10.1042/bj20111766.
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IDPs (intrinsically disordered proteins) are highly abundant in eukaryotic proteomes and important for cellular functions, especially in cell signalling and transcriptional regulation. An IDR (intrinsically disordered region) within an IDP often undergoes disorder-to-order transitions upon binding to various partners, allowing an IDP to recognize and bind different partners at various binding interfaces. Plant-specific GRAS proteins play critical and diverse roles in plant development and signalling, and act as integrators of signals from multiple plant growth regulatory and environmental inputs. Possessing an intrinsically disordered N-terminal domain, the GRAS proteins constitute the first functionally required unfoldome from the plant kingdom. Furthermore, the N-terminal domains of GRAS proteins contain MoRFs (molecular recognition features), short interaction-prone segments that are located within IDRs and are able to recognize their interacting partners by undergoing disorder-to-order transitions upon binding to these specific partners. These MoRFs represent potential protein–protein binding sites and may be acting as molecular bait in recognition events during plant development. Intrinsic disorder provides GRAS proteins with a degree of binding plasticity that may be linked to their functional versatility. As an overview of structure–function relationships for GRAS proteins, the present review covers the main biological functions of the GRAS family, the IDRs within these proteins and their implications for understanding mode-of-action.
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Roterman, Irena, Katarzyna Stapor, Piotr Fabian, and Leszek Konieczny. "New insights into disordered proteins and regions according to the FOD-M model." PLOS ONE 17, no. 10 (October 10, 2022): e0275300. http://dx.doi.org/10.1371/journal.pone.0275300.
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A collection of intrinsically disordered proteins (IDPs) having regions with the status of intrinsically disordered (IDR) according to the Disprot database was analyzed from the point of view of the structure of hydrophobic core in the structural unit (chain / domain). The analysis includes all the Homo Sapiens as well as Mus Musculus proteins present in the DisProt database for which the structure is available. In the analysis, the fuzzy oil drop modified model (FOD-M) was used, taking into account the external force field, modified by the presence of other factors apart from polar water, influencing protein structuring. The paper presents an alternative to secondary-structure-based classification of intrinsically disordered regions (IDR). The basis of our classification is the ordering of hydrophobic core as calculated by the FOD-M model resulting in FOD-ordered or FOD-unordered IDRs.
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Wilson, Carter J., Wing-Yiu Choy, and Mikko Karttunen. "AlphaFold2: A Role for Disordered Protein/Region Prediction?" International Journal of Molecular Sciences 23, no. 9 (April 21, 2022): 4591. http://dx.doi.org/10.3390/ijms23094591.
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The development of AlphaFold2 marked a paradigm-shift in the structural biology community. Herein, we assess the ability of AlphaFold2 to predict disordered regions against traditional sequence-based disorder predictors. We find that AlphaFold2 performs well at discriminating disordered regions, but also note that the disorder predictor one constructs from an AlphaFold2 structure determines accuracy. In particular, a naïve, but non-trivial assumption that residues assigned to helices, strands, and H-bond stabilized turns are likely ordered and all other residues are disordered results in a dramatic overestimation in disorder; conversely, the predicted local distance difference test (pLDDT) provides an excellent measure of residue-wise disorder. Furthermore, by employing molecular dynamics (MD) simulations, we note an interesting relationship between the pLDDT and secondary structure, that may explain our observations and suggests a broader application of the pLDDT for characterizing the local dynamics of intrinsically disordered proteins and regions (IDPs/IDRs).
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French-Pacheco, Leidys, Omar Rosas-Bringas, Lorenzo Segovia, and Alejandra A. Covarrubias. "Intrinsically disordered signaling proteins: Essential hub players in the control of stress responses in Saccharomyces cerevisiae." PLOS ONE 17, no. 3 (March 15, 2022): e0265422. http://dx.doi.org/10.1371/journal.pone.0265422.
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Cells have developed diverse mechanisms to monitor changes in their surroundings. This allows them to establish effective responses to cope with adverse environments. Some of these mechanisms have been well characterized in the budding yeast Saccharomyces cerevisiae, an excellent experimental model to explore and elucidate some of the strategies selected in eukaryotic organisms to adjust their growth and development in stressful conditions. The relevance of structural disorder in proteins and the impact on their functions has been uncovered for proteins participating in different processes. This is the case of some transcription factors (TFs) and other signaling hub proteins, where intrinsically disordered regions (IDRs) play a critical role in their function. In this work, we present a comprehensive bioinformatic analysis to evaluate the significance of structural disorder in those TFs (170) recognized in S. cerevisiae. Our findings show that 85.2% of these TFs contain at least one IDR, whereas ~30% exhibit a higher disorder level and thus were considered as intrinsically disordered proteins (IDPs). We also found that TFs contain a higher number of IDRs compared to the rest of the yeast proteins, and that intrinsically disordered TFs (IDTFs) have a higher number of protein-protein interactions than those with low structural disorder. The analysis of different stress response pathways showed a high content of structural disorder not only in TFs but also in other signaling proteins. The propensity of yeast proteome to undergo a liquid-liquid phase separation (LLPS) was also analyzed, showing that a significant proportion of IDTFs may undergo this phenomenon. Our analysis is a starting point for future research on the importance of structural disorder in yeast stress responses.
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Liu, Yumeng, Xiaolong Wang, and Bin Liu. "IDP–CRF: Intrinsically Disordered Protein/Region Identification Based on Conditional Random Fields." International Journal of Molecular Sciences 19, no. 9 (August 22, 2018): 2483. http://dx.doi.org/10.3390/ijms19092483.
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Accurate prediction of intrinsically disordered proteins/regions is one of the most important tasks in bioinformatics, and some computational predictors have been proposed to solve this problem. How to efficiently incorporate the sequence-order effect is critical for constructing an accurate predictor because disordered region distributions show global sequence patterns. In order to capture these sequence patterns, several sequence labelling models have been applied to this field, such as conditional random fields (CRFs). However, these methods suffer from certain disadvantages. In this study, we proposed a new computational predictor called IDP–CRF, which is trained on an updated benchmark dataset based on the MobiDB database and the DisProt database, and incorporates more comprehensive sequence-based features, including PSSMs (position-specific scoring matrices), kmer, predicted secondary structures, and relative solvent accessibilities. Experimental results on the benchmark dataset and two independent datasets show that IDP–CRF outperforms 25 existing state-of-the-art methods in this field, demonstrating that IDP–CRF is a very useful tool for identifying IDPs/IDRs (intrinsically disordered proteins/regions). We anticipate that IDP–CRF will facilitate the development of protein sequence analysis.
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Chu, Wen-Ting, and Jin Wang. "Thermodynamic and sequential characteristics of phase separation and droplet formation for an intrinsically disordered region/protein ensemble." PLOS Computational Biology 17, no. 3 (March 8, 2021): e1008672. http://dx.doi.org/10.1371/journal.pcbi.1008672.
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Liquid–liquid phase separation (LLPS) of some IDPs/IDRs can lead to the formation of the membraneless organelles in vitro and in vivo, which are essential for many biological processes in the cell. Here we select three different IDR segments of chaperon Swc5 and develop a polymeric slab model at the residue-level. By performing the molecular dynamics simulations, LLPS can be observed at low temperatures even without charge interactions and disappear at high temperatures. Both the sequence length and the charge pattern of the Swc5 segments can influence the critical temperature of LLPS. The results suggest that the effects of the electrostatic interactions on the LLPS behaviors can change significantly with the ratios and distributions of the charged residues, especially the sequence charge decoration (SCD) values. In addition, three different forms of swc conformation can be distinguished on the phase diagram, which is different from the conventional behavior of the free IDP/IDR. Both the packed form (the condensed-phase) and the dispersed form (the dilute-phase) of swc chains are found to be coexisted when LLPS occurs. They change to the fully-spread form at high temperatures. These findings will be helpful for the investigation of the IDP/IDR ensemble behaviors as well as the fundamental mechanism of the LLPS process in bio-systems.
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Bianchi, Greta, Stefania Brocca, Sonia Longhi, and Vladimir N. Uversky. "Liaisons dangereuses: Intrinsic Disorder in Cellular Proteins Recruited to Viral Infection-Related Biocondensates." International Journal of Molecular Sciences 24, no. 3 (January 21, 2023): 2151. http://dx.doi.org/10.3390/ijms24032151.
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Liquid–liquid phase separation (LLPS) is responsible for the formation of so-called membrane-less organelles (MLOs) that are essential for the spatio-temporal organization of the cell. Intrinsically disordered proteins (IDPs) or regions (IDRs), either alone or in conjunction with nucleic acids, are involved in the formation of these intracellular condensates. Notably, viruses exploit LLPS at their own benefit to form viral replication compartments. Beyond giving rise to biomolecular condensates, viral proteins are also known to partition into cellular MLOs, thus raising the question as to whether these cellular phase-separating proteins are drivers of LLPS or behave as clients/regulators. Here, we focus on a set of eukaryotic proteins that are either sequestered in viral factories or colocalize with viral proteins within cellular MLOs, with the primary goal of gathering organized, predicted, and experimental information on these proteins, which constitute promising targets for innovative antiviral strategies. Using various computational approaches, we thoroughly investigated their disorder content and inherent propensity to undergo LLPS, along with their biological functions and interactivity networks. Results show that these proteins are on average, though to varying degrees, enriched in disorder, with their propensity for phase separation being correlated, as expected, with their disorder content. A trend, which awaits further validation, tends to emerge whereby the most disordered proteins serve as drivers, while more ordered cellular proteins tend instead to be clients of viral factories. In light of their high disorder content and their annotated LLPS behavior, most proteins in our data set are drivers or co-drivers of molecular condensation, foreshadowing a key role of these cellular proteins in the scaffolding of viral infection-related MLOs.
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Beveridge, Rebecca, and Antonio N. Calabrese. "Structural Proteomics Methods to Interrogate the Conformations and Dynamics of Intrinsically Disordered Proteins." Frontiers in Chemistry 9 (March 11, 2021). http://dx.doi.org/10.3389/fchem.2021.603639.
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Intrinsically disordered proteins (IDPs) and regions of intrinsic disorder (IDRs) are abundant in proteomes and are essential for many biological processes. Thus, they are often implicated in disease mechanisms, including neurodegeneration and cancer. The flexible nature of IDPs and IDRs provides many advantages, including (but not limited to) overcoming steric restrictions in binding, facilitating posttranslational modifications, and achieving high binding specificity with low affinity. IDPs adopt a heterogeneous structural ensemble, in contrast to typical folded proteins, making it challenging to interrogate their structure using conventional tools. Structural mass spectrometry (MS) methods are playing an increasingly important role in characterizing the structure and function of IDPs and IDRs, enabled by advances in the design of instrumentation and the development of new workflows, including in native MS, ion mobility MS, top-down MS, hydrogen-deuterium exchange MS, crosslinking MS, and covalent labeling. Here, we describe the advantages of these methods that make them ideal to study IDPs and highlight recent applications where these tools have underpinned new insights into IDP structure and function that would be difficult to elucidate using other methods.
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Quaglia, Federica, Anastasia Chasapi, Maria Victoria Nugnes, Maria Cristina Aspromonte, Emanuela Leonardi, Damiano Piovesan, and Silvio C. E. Tosatto. "Best practices for the manual curation of intrinsically disordered proteins in DisProt." Database 2024 (January 1, 2024). http://dx.doi.org/10.1093/database/baae009.
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Abstract The DisProt database is a resource containing manually curated data on experimentally validated intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) from the literature. Developed in 2005, its primary goal was to collect structural and functional information into proteins that lack a fixed three-dimensional structure. Today, DisProt has evolved into a major repository that not only collects experimental data but also contributes to our understanding of the IDPs/IDRs roles in various biological processes, such as autophagy or the life cycle mechanisms in viruses or their involvement in diseases (such as cancer and neurodevelopmental disorders). DisProt offers detailed information on the structural states of IDPs/IDRs, including state transitions, interactions and their functions, all provided as curated annotations. One of the central activities of DisProt is the meticulous curation of experimental data from the literature. For this reason, to ensure that every expert and volunteer curator possesses the requisite knowledge for data evaluation, collection and integration, training courses and curation materials are available. However, biocuration guidelines concur on the importance of developing robust guidelines that not only provide critical information about data consistency but also ensure data acquisition.This guideline aims to provide both biocurators and external users with best practices for manually curating IDPs and IDRs in DisProt. It describes every step of the literature curation process and provides use cases of IDP curation within DisProt. Database URL: https://disprot.org/
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Bondos, Sarah E., A. Keith Dunker, and Vladimir N. Uversky. "On the roles of intrinsically disordered proteins and regions in cell communication and signaling." Cell Communication and Signaling 19, no. 1 (August 30, 2021). http://dx.doi.org/10.1186/s12964-021-00774-3.
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AbstractFor proteins, the sequence → structure → function paradigm applies primarily to enzymes, transmembrane proteins, and signaling domains. This paradigm is not universal, but rather, in addition to structured proteins, intrinsically disordered proteins and regions (IDPs and IDRs) also carry out crucial biological functions. For these proteins, the sequence → IDP/IDR ensemble → function paradigm applies primarily to signaling and regulatory proteins and regions. Often, in order to carry out function, IDPs or IDRs cooperatively interact, either intra- or inter-molecularly, with structured proteins or other IDPs or intermolecularly with nucleic acids. In this IDP/IDR thematic collection published in Cell Communication and Signaling, thirteen articles are presented that describe IDP/IDR signaling molecules from a variety of organisms from humans to fruit flies and tardigrades (“water bears”) and that describe how these proteins and regions contribute to the function and regulation of cell signaling. Collectively, these papers exhibit the diverse roles of disorder in responding to a wide range of signals as to orchestrate an array of organismal processes. They also show that disorder contributes to signaling in a broad spectrum of species, ranging from micro-organisms to plants and animals.
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Liu, Yumeng, Xiaolong Wang, and Bin Liu. "RFPR-IDP: reduce the false positive rates for intrinsically disordered protein and region prediction by incorporating both fully ordered proteins and disordered proteins." Briefings in Bioinformatics, February 28, 2020. http://dx.doi.org/10.1093/bib/bbaa018.
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Abstract As an important type of proteins, intrinsically disordered proteins/regions (IDPs/IDRs) are related to many crucial biological functions. Accurate prediction of IDPs/IDRs is beneficial to the prediction of protein structures and functions. Most of the existing methods ignore the fully ordered proteins without IDRs during training and test processes. As a result, the corresponding predictors prefer to predict the fully ordered proteins as disordered proteins. Unfortunately, these methods were only evaluated on datasets consisting of disordered proteins without or with only a few fully ordered proteins, and therefore, this problem escapes the attention of the researchers. However, most of the newly sequenced proteins are fully ordered proteins in nature. These predictors fail to accurately predict the ordered and disordered proteins in real-world applications. In this regard, we propose a new method called RFPR-IDP trained with both fully ordered proteins and disordered proteins, which is constructed based on the combination of convolution neural network (CNN) and bidirectional long short-term memory (BiLSTM). The experimental results show that although the existing predictors perform well for predicting the disordered proteins, they tend to predict the fully ordered proteins as disordered proteins. In contrast, the RFPR-IDP predictor can correctly predict the fully ordered proteins and outperform the other 10 state-of-the-art methods when evaluated on a test dataset with both fully ordered proteins and disordered proteins. The web server and datasets of RFPR-IDP are freely available at http://bliulab.net/RFPR-IDP/server.
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Howton, T. C., Yingqian Ada Zhan, Yali Sun, and M. Shahid Mukhtar. "Intrinsically disordered proteins: controlled chaos or random walk." International Journal of Plant Biology 6, no. 1 (February 9, 2016). http://dx.doi.org/10.4081/pb.2015.6191.
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Traditional conventions that a protein’s sequence dictates its definitive, tertiary structure, and that this fixed structure provides the protein with the ability to carry out its designated role(s) are still correct but not for all proteins. Research over the past decade discovered that several key proteins possess intrinsically disordered regions (IDRs) that are crucial to their ability to perform specific functions and are observed clustered together within important classes of proteins. In this review, we aim to demonstrate how free energy landscapes, molecular dynamics simulations, and homology modeling are helpful in understanding key conformational dynamics of intrinsically disordered proteins (IDPs). Additionally, we use a list of predicted IDPs found in Arabidopsis to identify chromatin organizers and transcriptional regulators as being highly enriched in IDPs. Furthermore, we focus our attention to specific proteins within these families such as HAC5, EFS, ANAC019, ANAC013, and ANAC046. Future studies are needed to experimentally identify additional IDPs and their binding mechanisms.
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Iserte, Javier A., Tamas Lazar, Silvio C. E. Tosatto, Peter Tompa, and Cristina Marino-Buslje. "Chasing coevolutionary signals in intrinsically disordered proteins complexes." Scientific Reports 10, no. 1 (October 21, 2020). http://dx.doi.org/10.1038/s41598-020-74791-6.
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Abstract Intrinsically disordered proteins/regions (IDPs/IDRs) are crucial components of the cell, they are highly abundant and participate ubiquitously in a wide range of biological functions, such as regulatory processes and cell signaling. Many of their important functions rely on protein interactions, by which they trigger or modulate different pathways. Sequence covariation, a powerful tool for protein contact prediction, has been applied successfully to predict protein structure and to identify protein–protein interactions mostly of globular proteins. IDPs/IDRs also mediate a plethora of protein–protein interactions, highlighting the importance of addressing sequence covariation-based inter-protein contact prediction of this class of proteins. Despite their importance, a systematic approach to analyze the covariation phenomena of intrinsically disordered proteins and their complexes is still missing. Here we carry out a comprehensive critical assessment of coevolution-based contact prediction in IDP/IDR complexes and detail the challenges and possible limitations that emerge from their analysis. We found that the coevolutionary signal is faint in most of the complexes of disordered proteins but positively correlates with the interface size and binding affinity between partners. In addition, we discuss the state-of-art methodology by biological interpretation of the results, formulate evaluation guidelines and suggest future directions of development to the field.
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Sigrist, Stephan J., and Volker Haucke. "Orchestrating vesicular and nonvesicular membrane dynamics by intrinsically disordered proteins." EMBO reports, September 8, 2023. http://dx.doi.org/10.15252/embr.202357758.
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AbstractCompartmentalization by membranes is a common feature of eukaryotic cells and serves to spatiotemporally confine biochemical reactions to control physiology. Membrane‐bound organelles such as the endoplasmic reticulum (ER), the Golgi complex, endosomes and lysosomes, and the plasma membrane, continuously exchange material via vesicular carriers. In addition to vesicular trafficking entailing budding, fission, and fusion processes, organelles can form membrane contact sites (MCSs) that enable the nonvesicular exchange of lipids, ions, and metabolites, or the secretion of neurotransmitters via subsequent membrane fusion. Recent data suggest that biomolecule and information transfer via vesicular carriers and via MCSs share common organizational principles and are often mediated by proteins with intrinsically disordered regions (IDRs). Intrinsically disordered proteins (IDPs) can assemble via low‐affinity, multivalent interactions to facilitate membrane tethering, deformation, fission, or fusion. Here, we review our current understanding of how IDPs drive the formation of multivalent protein assemblies and protein condensates to orchestrate vesicular and nonvesicular transport with a special focus on presynaptic neurotransmission. We further discuss how dysfunction of IDPs causes disease and outline perspectives for future research.
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Roterman, Irena, Katarzyna Stapor, and Leszek Konieczny. "Engagement of intrinsic disordered proteins in protein–protein interaction." Frontiers in Molecular Biosciences 10 (July 31, 2023). http://dx.doi.org/10.3389/fmolb.2023.1230922.
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Proteins from the intrinsically disordered group (IDP) focus the attention of many researchers engaged in protein structure analysis. The main criteria used in their identification are lack of secondary structure and significant structural variability. This variability takes forms that cannot be identified in the X-ray technique. In the present study, different criteria were used to assess the status of IDP proteins and their fragments recognized as intrinsically disordered regions (IDRs). The status of the hydrophobic core in proteins identified as IDPs and in their complexes was assessed. The status of IDRs as components of the ordering structure resulting from the construction of the hydrophobic core was also assessed. The hydrophobic core is understood as a structure encompassing the entire molecule in the form of a centrally located high concentration of hydrophobicity and a shell with a gradually decreasing level of hydrophobicity until it reaches a level close to zero on the protein surface. It is a model assuming that the protein folding process follows a micellization pattern aiming at exposing polar residues on the surface, with the simultaneous isolation of hydrophobic amino acids from the polar aquatic environment. The use of the model of hydrophobicity distribution in proteins in the form of the 3D Gaussian distribution described on the protein particle introduces the possibility of assessing the degree of similarity to the assumed micelle-like distribution and also enables the identification of deviations and mismatch between the actual distribution and the idealized distribution. The FOD (fuzzy oil drop) model and its modified FOD-M version allow for the quantitative assessment of these differences and the assessment of the relationship of these areas to the protein function. In the present work, the sections of IDRs in protein complexes classified as IDPs are analyzed. The classification “disordered” in the structural sense (lack of secondary structure or high flexibility) does not always entail a mismatch with the structure of the hydrophobic core. Particularly, the interface area, often consisting of IDRs, in many analyzed complexes shows the compliance of the hydrophobicity distribution with the idealized distribution, which proves that matching to the structure of the hydrophobic core does not require secondary structure ordering.
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Zhang, Zhengjian, Zarko Boskovic, Mahmud M. Hussain, Wenxin Hu, Carla Inouye, Han-Je Kim, A. Katherine Abole, et al. "Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation." eLife 4 (August 28, 2015). http://dx.doi.org/10.7554/elife.07777.
Full textAbstract:
Intrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. In this study, we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex. Binding arrests an isomerization of promoter-bound TFIID that is required for the engagement of Pol II during the first (de novo) round of transcription initiation. However, the specific chemical probe does not affect reinitiation, which requires the re-entry of Pol II, thus, mechanistically distinguishing these two modes of transcription initiation. This work also suggests a new avenue for targeting the elusive IDRs by harnessing certain features of metal-based complexes for mechanistic studies, and for the development of novel pharmaceutical interventions.
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Pang, Yihe, and Bin Liu. "DisoFLAG: accurate prediction of protein intrinsic disorder and its functions using graph-based interaction protein language model." BMC Biology 22, no. 1 (January 2, 2024). http://dx.doi.org/10.1186/s12915-023-01803-y.
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AbstractIntrinsically disordered proteins and regions (IDPs/IDRs) are functionally important proteins and regions that exist as highly dynamic conformations under natural physiological conditions. IDPs/IDRs exhibit a broad range of molecular functions, and their functions involve binding interactions with partners and remaining native structural flexibility. The rapid increase in the number of proteins in sequence databases and the diversity of disordered functions challenge existing computational methods for predicting protein intrinsic disorder and disordered functions. A disordered region interacts with different partners to perform multiple functions, and these disordered functions exhibit different dependencies and correlations. In this study, we introduce DisoFLAG, a computational method that leverages a graph-based interaction protein language model (GiPLM) for jointly predicting disorder and its multiple potential functions. GiPLM integrates protein semantic information based on pre-trained protein language models into graph-based interaction units to enhance the correlation of the semantic representation of multiple disordered functions. The DisoFLAG predictor takes amino acid sequences as the only inputs and provides predictions of intrinsic disorder and six disordered functions for proteins, including protein-binding, DNA-binding, RNA-binding, ion-binding, lipid-binding, and flexible linker. We evaluated the predictive performance of DisoFLAG following the Critical Assessment of protein Intrinsic Disorder (CAID) experiments, and the results demonstrated that DisoFLAG offers accurate and comprehensive predictions of disordered functions, extending the current coverage of computationally predicted disordered function categories. The standalone package and web server of DisoFLAG have been established to provide accurate prediction tools for intrinsic disorders and their associated functions.
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Cubuk, Jasmine, Melissa D. Stuchell-Brereton, and Andrea Soranno. "The biophysics of disordered proteins from the point of view of single-molecule fluorescence spectroscopy." Essays in Biochemistry, November 23, 2022. http://dx.doi.org/10.1042/ebc20220065.
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Abstract Intrinsically disordered proteins (IDPs) and regions (IDRs) have emerged as key players across many biological functions and diseases. Differently from structured proteins, disordered proteins lack stable structure and are particularly sensitive to changes in the surrounding environment. Investigation of disordered ensembles requires new approaches and concepts for quantifying conformations, dynamics, and interactions. Here, we provide a short description of the fundamental biophysical properties of disordered proteins as understood through the lens of single-molecule fluorescence observations. Single-molecule Förster resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS) provides an extensive and versatile toolbox for quantifying the characteristics of conformational distributions and the dynamics of disordered proteins across many different solution conditions, both in vitro and in living cells.
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Gandass, Nishu, Kajal, and Prafull Salvi. "Intrinsically disordered protein, DNA binding with one finger transcription factor (OsDOF27) implicates thermotolerance in yeast and rice." Frontiers in Plant Science 13 (July 29, 2022). http://dx.doi.org/10.3389/fpls.2022.956299.
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Intrinsically disorder regions or proteins (IDRs or IDPs) constitute a large subset of the eukaryotic proteome, which challenges the protein structure–function paradigm. These IDPs lack a stable tertiary structure, yet they play a crucial role in the diverse biological process of plants. This study represents the intrinsically disordered nature of a plant-specific DNA binding with one finger transcription factor (DOF-TF). Here, we have investigated the role of OsDOF27 and characterized it as an intrinsically disordered protein. Furthermore, the molecular role of OsDOF27 in thermal stress tolerance has been elucidated. The qRT-PCR analysis revealed that OsDOF27 was significantly upregulated under different abiotic stress treatments in rice, particularly under heat stress. The stress-responsive transcript induction of OsDOF27 was further correlated with enriched abiotic stress-related cis-regulatory elements present in its promoter region. The in vivo functional analysis of the potential role of OsDOF27 in thermotolerance was further studied in yeast and in planta. Ectopic expression of OsDOF27 in yeast implicates thermotolerance response. Furthermore, the rice transgenic lines with overexpressing OsDOF27 revealed a positive role in mitigating heat stress tolerance. Collectively, our results evidently show the intrinsically disorderedness in OsDOF27 and its role in thermal stress response in rice.
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Chen, Serena H., Kevin L. Weiss, Christopher Stanley, and Debsindhu Bhowmik. "Structural characterization of an intrinsically disordered protein complex using integrated small‐angle neutron scattering and computing." Protein Science, August 30, 2023. http://dx.doi.org/10.1002/pro.4772.
Full textAbstract:
AbstractCharacterizing structural ensembles of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins is essential for studying structure‐function relationships. Due to different neutron scattering lengths of hydrogen and deuterium, selective labeling and contrast matching in small‐angle neutron scattering (SANS) becomes an effective tool to study dynamic structures of disordered systems. However, experimental timescales typically capture measurements averaged over multiple conformations, leaving complex SANS data for disentanglement. We hereby demonstrate an integrated method to elucidate the structural ensemble of a complex formed by two IDRs. We use data from both full contrast and contrast matching with residue‐specific deuterium labeling SANS experiments, microsecond all‐atom molecular dynamics (MD) simulations with four molecular mechanics force fields, and an autoencoder‐based deep learning (DL) algorithm. From our combined approach, we show that selective deuteration provides additional information that helps characterize structural ensembles. We find that among the four force fields, a99SB‐disp and CHARMM36m show the strongest agreement with SANS and NMR experiments. In addition, our DL algorithm not only complements conventional structural analysis methods but also successfully differentiates NMR and MD structures which are indistinguishable on the free energy surface. Lastly, we present an ensemble that describes experimental SANS and NMR data better than MD ensembles generated by one single force field and reveal three clusters of distinct conformations. Our results demonstrate a new integrated approach for characterizing structural ensembles of IDPs.This article is protected by copyright. All rights reserved.
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Avni, Anamika, Ashish Joshi, Anuja Walimbe, Swastik G. Pattanashetty, and Samrat Mukhopadhyay. "Single-droplet surface-enhanced Raman scattering decodes the molecular determinants of liquid-liquid phase separation." Nature Communications 13, no. 1 (July 28, 2022). http://dx.doi.org/10.1038/s41467-022-32143-0.
Full textAbstract:
AbstractBiomolecular condensates formed via liquid-liquid phase separation (LLPS) are involved in a myriad of critical cellular functions and debilitating neurodegenerative diseases. Elucidating the role of intrinsic disorder and conformational heterogeneity of intrinsically disordered proteins/regions (IDPs/IDRs) in these phase-separated membrane-less organelles is crucial to understanding the mechanism of formation and regulation of biomolecular condensates. Here we introduce a unique single-droplet surface-enhanced Raman scattering (SERS) methodology that utilizes surface-engineered, plasmonic, metal nanoparticles to unveil the inner workings of mesoscopic liquid droplets of Fused in Sarcoma (FUS) in the absence and presence of RNA. These highly sensitive measurements offer unprecedented sensitivity to capture the crucial interactions, conformational heterogeneity, and structural distributions within the condensed phase in a droplet-by-droplet manner. Such an ultra-sensitive single-droplet vibrational methodology can serve as a potent tool to decipher the key molecular drivers of biological phase transitions of a wide range of biomolecular condensates involved in physiology and disease.
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Di Ianni, Alessio, Christian Tüting, Marc Kipping, Christian H. Ihling, Janett Köppen, Claudio Iacobucci, Christian Arlt, Panagiotis L. Kastritis, and Andrea Sinz. "Structural assessment of the full-length wild-type tumor suppressor protein p53 by mass spectrometry-guided computational modeling." Scientific Reports 13, no. 1 (May 25, 2023). http://dx.doi.org/10.1038/s41598-023-35437-5.
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AbstractThe tetrameric tumor suppressor p53 represents a great challenge for 3D-structural analysis due to its high degree of intrinsic disorder (ca. 40%). We aim to shed light on the structural and functional roles of p53’s C-terminal region in full-length, wild-type human p53 tetramer and their importance for DNA binding. For this, we employed complementary techniques of structural mass spectrometry (MS) in an integrated approach with computational modeling. Our results show no major conformational differences in p53 between DNA-bound and DNA-free states, but reveal a substantial compaction of p53’s C-terminal region. This supports the proposed mechanism of unspecific DNA binding to the C-terminal region of p53 prior to transcription initiation by specific DNA binding to the core domain of p53. The synergies between complementary structural MS techniques and computational modeling as pursued in our integrative approach is envisioned to serve as general strategy for studying intrinsically disordered proteins (IDPs) and intrinsically disordered region (IDRs).
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Chow, Vimanda, Esther Wolf, Cristina Lento, and Derek J. Wilson. "Developments in rapid hydrogen–deuterium exchange methods." Essays in Biochemistry, January 13, 2023. http://dx.doi.org/10.1042/ebc20220174.
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Abstract Biological macromolecules, such as proteins, nucleic acids, and carbohydrates, contain heteroatom-bonded hydrogens that undergo exchange with solvent hydrogens on timescales ranging from microseconds to hours. In hydrogen–deuterium exchange mass spectrometry (HDX-MS), this exchange process is used to extract information about biomolecular structure and dynamics. This minireview focuses on millisecond timescale HDX-MS measurements, which, while less common than ‘conventional’ timescale (seconds to hours) HDX-MS, provide a unique window into weakly structured species, weak (or fast cycling) binding interactions, and subtle shifts in conformational dynamics. This includes intrinsically disordered proteins and regions (IDPs/IDRs) that are associated with cancer and amyloidotic neurodegenerative disease. For nucleic acids and carbohydrates, structures such as isomers, stems, and loops, can be elucidated and overall structural rigidity can be assessed. We will provide a brief overview of technical developments in rapid HDX followed by highlights of various applications, emphasising the importance of broadening the HDX timescale to improve throughput and to capture a wider range of function-relevant dynamic and structural shifts.
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Shafat, Zoya, Anwar Ahmed, Mohammad K. Parvez, and Shama Parveen. "Intrinsic disorder in the open reading frame 2 of hepatitis E virus: a protein with multiple functions beyond viral capsid." Journal of Genetic Engineering and Biotechnology 21, no. 1 (March 16, 2023). http://dx.doi.org/10.1186/s43141-023-00477-x.
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Abstract Background Hepatitis E virus (HEV) is the cause of a liver disease hepatitis E. The translation product of HEV ORF2 has recently been demonstrated as a protein involved in multiple functions besides performing its major role of a viral capsid. As intrinsically disordered regions (IDRs) are linked to various essential roles in the virus’s life cycle, we analyzed the disorder pattern distribution of the retrieved ORF2 protein sequences by employing different online predictors. Our findings might provide some clues on the disorder-based functions of ORF2 protein that possibly help us in understanding its behavior other than as a HEV capsid protein. Results The modeled three dimensional (3D) structures of ORF2 showed the predominance of random coils or unstructured regions in addition to major secondary structure components (alpha helix and beta strand). After initial scrutinization, the predictors VLXT and VSL2 predicted ORF2 as a highly disordered protein while the predictors VL3 and DISOPRED3 predicted ORF2 as a moderately disordered protein, thus categorizing HEV-ORF2 into IDP (intrinsically disordered protein) or IDPR (intrinsically disordered protein region) respectively. Thus, our initial predicted disorderness in ORF2 protein 3D structures was in excellent agreement with their predicted disorder distribution patterns (evaluated through different predictors). The abundance of MoRFs (disorder-based protein binding sites) in ORF2 was observed that signified their interaction with binding partners which might further assist in viral infection. As IDPs/IDPRs are targets of regulation, we carried out the phosphorylation analysis to reveal the presence of post-translationally modified sites. Prevalence of several disordered-based phosphorylation sites further signified the involvement of ORF2 in diverse and significant biological processes. Furthermore, ORF2 structure-associated functions revealed its involvement in several crucial functions and biological processes like binding and catalytic activities. Conclusions The results predicted ORF2 as a protein with multiple functions besides its role as a capsid protein. Moreover, the occurrence of IDPR/IDP in ORF2 protein suggests that its disordered region might serve as novel drug targets via functioning as potential interacting domains. Our data collectively might provide significant implication in HEV vaccine search as disorderness in viral proteins is related to mechanisms involved in immune evasion.
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Liu, Zi Hao, João M. C. Teixeira, Oufan Zhang, Thomas E. Tsangaris, Jie Li, Claudiu C. Gradinaru, Teresa Head-Gordon, and Julie D. Forman-Kay. "Local Disordered Region Sampling (LDRS) for Ensemble Modeling of Proteins with Experimentally Undetermined or Low Confidence Prediction Segments." Bioinformatics, December 7, 2023. http://dx.doi.org/10.1093/bioinformatics/btad739.
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Abstract Summary The Local Disordered Region Sampling (LDRS, pronounced loaders) tool is a new module developed for IDPConformerGenerator (Teixeira et al. 2022), a previously validated approach to model intrinsically disordered proteins (IDPs). The IDPConformerGenerator LDRS module provides a method for generating all-atom conformations of intrinsically disordered regions (IDRs) at N- and C-termini of and in loops or linkers between folded regions of an existing protein structure. These disordered elements often lead to missing coordinates in experimental structures or low confidence in predicted structures. Requiring only a pre-existing PDB or mmCIF formatted structural template of the protein with missing coordinates or with predicted confidence scores and its full-length primary sequence, LDRS will automatically generate physically meaningful conformational ensembles of the missing flexible regions to complete the full-length protein. The capabilities of the LDRS tool of IDPConformerGenerator include modeling phosphorylation sites using enhanced Monte Carlo Side Chain Entropy (MC-SCE) (Bhowmick and Head-Gordon 2015), transmembrane proteins within an all-atom bilayer, and multi-chain complexes. The modeling capacity of LDRS capitalizes on the modularity, the ability to be used as a library and via command-line, and the computational speed of the IDPConformerGenerator platform. Availability and Implementation The LDRS module is part of the IDPConformerGenerator modeling suite, which can be downloaded from GitHub at https://github.com/julie-forman-kay-lab/IDPConformerGenerator. IDPConformerGenerator is written in Python3 and works on Linux, Microsoft Windows, and Mac OS versions that support DSSP. Users can utilize LDRS’s Python API for scripting the same way they can use any part of IDPConformerGenerator’s API, by importing functions from the `idpconfgen.ldrs_helper` library. Otherwise, LDRS can be used as a command line interface application within IDPConformerGenerator. Full documentation is available within the command-line interface (CLI) as well as on IDPConformerGenerator’s official documentation pages (https://idpconformergenerator.readthedocs.io/en/latest/). Contact For support with LDRS please contact Zi Hao (Nemo) Liu via nemo.liu@sickkids.ca or submit an issue in the IDPConformerGenerator repository on GitHub (https://github.com/julie-forman-kay-lab/IDPConformerGenerator/issues). Supplementary Information The supplementary information document found on Bioinformatics online contains, or links to, all the conformer ensembles generated for this publication, the generalized Python scripts using the LDRS Python API, figures of detailed methods, fractional secondary structure information, torsion angle sampling, and the time required to generate the different protein cases.