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Browsing by Author "Oldfield, Christopher J."
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Item Classification of Intrinsically Disordered Regions and Proteins(American Chemical Society, 2014-07-09) van der Lee, Robin; Buljan, Marija; Lang, Benjamin; Weatheritt, Robert J.; Daughdrill, Gary W.; Dunker, A. Keith; Fuxreiter, Monika; Gough, Julian; Gsponer, Joerg; Jones, David T.; Kim, Philip M.; Kriwacki, Richard W.; Oldfield, Christopher J.; Pappu, Rohit V.; Tompa, Peter; Uversky, Vladimir N.; Wright, Peter E.; Babu, M. Madan; Department of Biochemistry & Molecular Biology, IU School of MedicineItem A creature with a hundred waggly tails: intrinsically disordered proteins in the ribosome(Springer Nature, 2014) Peng, Zhenling; Oldfield, Christopher J.; Xue, Bin; Mizianty, Marcin J.; Dunker, A. Keith; Kurgan, Lukasz; Uversky, Vladmir N.; Biochemistry & Molecular Biology, IU School of MedicineIntrinsic disorder (i.e., lack of a unique 3-D structure) is a common phenomenon, and many biologically active proteins are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions constitute a significant part of all proteomes, and their functional repertoire is complementary to functions of ordered proteins. In fact, intrinsic disorder represents an important driving force for many specific functions. An illustrative example of such disorder-centric functional class is RNA-binding proteins. In this study, we present the results of comprehensive bioinformatics analyses of the abundance and roles of intrinsic disorder in 3,411 ribosomal proteins from 32 species. We show that many ribosomal proteins are intrinsically disordered or hybrid proteins that contain ordered and disordered domains. Predicted globular domains of many ribosomal proteins contain noticeable regions of intrinsic disorder. We also show that disorder in ribosomal proteins has different characteristics compared to other proteins that interact with RNA and DNA including overall abundance, evolutionary conservation, and involvement in protein–protein interactions. Furthermore, intrinsic disorder is not only abundant in the ribosomal proteins, but we demonstrate that it is absolutely necessary for their various functions.Item A creature with a hundred waggly tails: intrinsically disordered proteins in the ribosome(Springer, 2013-08-13) Peng, Zhenling; Oldfield, Christopher J.; Xue, Bin; Mizianty, Marcin J.; Dunker, A. Keith; Kurgan, Lukasz; Uversky, Vladimir N.; Biochemistry and Molecular Biology, School of MedicineIntrinsic disorder (i.e., lack of a unique 3-D structure) is a common phenomenon, and many biologically active proteins are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions constitute a significant part of all proteomes, and their functional repertoire is complementary to functions of ordered proteins. In fact, intrinsic disorder represents an important driving force for many specific functions. An illustrative example of such disorder-centric functional class is RNA-binding proteins. In this study, we present the results of comprehensive bioinformatics analyses of the abundance and roles of intrinsic disorder in 3,411 ribosomal proteins from 32 species. We show that many ribosomal proteins are intrinsically disordered or hybrid proteins that contain ordered and disordered domains. Predicted globular domains of many ribosomal proteins contain noticeable regions of intrinsic disorder. We also show that disorder in ribosomal proteins has different characteristics compared to other proteins that interact with RNA and DNA including overall abundance, evolutionary conservation, and involvement in protein–protein interactions. Furthermore, intrinsic disorder is not only abundant in the ribosomal proteins, but we demonstrate that it is absolutely necessary for their various functions.Item DescribePROT: database of amino acid-level protein structure and function predictions(Oxford University Press, 2021-01-08) Zhao, Bi; Katuwawala, Akila; Oldfield, Christopher J.; Dunker, A. Keith; Faraggi, Eshel; Gsponer, Jörg; Kloczkowski, Andrzej; Malhis, Nawar; Mirdita, Milot; Obradovic, Zoran; Söding, Johannes; Steinegger, Martin; Zhou, Yaoqi; Kurgan, Lukasz; Medicine, School of MedicineWe present DescribePROT, the database of predicted amino acid-level descriptors of structure and function of proteins. DescribePROT delivers a comprehensive collection of 13 complementary descriptors predicted using 10 popular and accurate algorithms for 83 complete proteomes that cover key model organisms. The current version includes 7.8 billion predictions for close to 600 million amino acids in 1.4 million proteins. The descriptors encompass sequence conservation, position specific scoring matrix, secondary structure, solvent accessibility, intrinsic disorder, disordered linkers, signal peptides, MoRFs and interactions with proteins, DNA and RNAs. Users can search DescribePROT by the amino acid sequence and the UniProt accession number and entry name. The pre-computed results are made available instantaneously. The predictions can be accesses via an interactive graphical interface that allows simultaneous analysis of multiple descriptors and can be also downloaded in structured formats at the protein, proteome and whole database scale. The putative annotations included by DescriPROT are useful for a broad range of studies, including: investigations of protein function, applied projects focusing on therapeutics and diseases, and in the development of predictors for other protein sequence descriptors. Future releases will expand the coverage of DescribePROT. DescribePROT can be accessed at http://biomine.cs.vcu.edu/servers/DESCRIBEPROT/.Item DisProt 7.0: a major update of the database of disordered proteins(Oxford University Press, 2017-01-04) Piovesan, Damiano; Tabaro, Francesco; Micetic, Ivan; Necci, Marco; Quaglia, Federica; Oldfield, Christopher J.; Aspromonte, Maria Cristina; Davey, Norman E.; Davidovic, Radoslav; Dosztanyi, Zsuzsanna; Elofsson, Arne; Gasparini, Alessandra; Hatos, Andras; Kajava, Andrey V.; Kalmar, Lajos; Leonardi, Emanuela; Lazar, Tamas; Macedo-Ribeiro, Sandra; Macossay-Castillo, Mauricio; Meszaros, Attila; Minervini, Giovanni; Murvai, Nikoletta; Pujols, Jordi; Roche, Daniel B.; Salladini, Edoardo; Schad, Eva; Schramm, Antoine; Szabo, Beata; Tantos, Agnes; Tonello, Fiorella; Tsirigos, Konstantinos D.; Veljkovic, Nevena; Ventura, Salvador; Vranken, Wim; Warholm, Per; Uversky, Vladimir N.; Dunker, A. Keith; Longhi, Sonia; Tompa, Peter; Tosatto, Silvio C.E.; Department of Biochemistry and Molecular Biology, IU School of MedicineThe Database of Protein Disorder (DisProt, URL: www.disprot.org) has been significantly updated and upgraded since its last major renewal in 2007. The current release holds information on more than 800 entries of IDPs/IDRs, i.e. intrinsically disordered proteins or regions that exist and function without a well-defined three-dimensional structure. We have re-curated previous entries to purge DisProt from conflicting cases, and also upgraded the functional classification scheme to reflect continuous advance in the field in the past 10 years or so. We define IDPs as proteins that are disordered along their entire sequence, i.e. entirely lack structural elements, and IDRs as regions that are at least five consecutive residues without well-defined structure. We base our assessment of disorder strictly on experimental evidence, such as X-ray crystallography and nuclear magnetic resonance (primary techniques) and a broad range of other experimental approaches (secondary techniques). Confident and ambiguous annotations are highlighted separately. DisProt 7.0 presents classified knowledge regarding the experimental characterization and functional annotations of IDPs/IDRs, and is intended to provide an invaluable resource for the research community for a better understanding structural disorder and for developing better computational tools for studying disordered proteins.Item Evidence for a Strong Correlation Between Transcription Factor Protein Disorder and Organismic Complexity(Oxford University Press, 2017-05-01) Yruela, Inmaculada; Oldfield, Christopher J.; Niklas, Karl J.; Dunker, A. Keith; Department of Biochemistry and Molecular Biology, School of MedicineStudies of diverse phylogenetic lineages reveal that protein disorder increases in concert with organismic complexity but that differences nevertheless exist among lineages. To gain insight into this phenomenology, we analyzed all of the transcription factor (TF) families for which sequences are known for 17 species spanning bacteria, yeast, algae, land plants, and animals and for which the number of different cell types has been reported in the primary literature. Although the fraction of disordered residues in TF sequences is often moderately or poorly correlated with organismic complexity as gauged by cell-type number (r2 < 0.5), an unbiased and phylogenetically broad analysis shows that organismic complexity is positively and strongly correlated with the total number of TFs, the number of their spliced variants and their total disordered residues content (r2 > 0.8). Furthermore, the correlation between the fraction of disordered residues and cell-type number becomes stronger when confined to the TF families participating in cell cycle, cell size, cell division, cell differentiation, or cell proliferation, and other important developmental processes. The data also indicate that evolutionarily simpler organisms allow for the detection of subtle differences in the conserved IDRs of TFs as well as changes in variable IDRs, which can influence the DNA recognition and multifunctionality of TFs through direct or indirect mechanisms. Although strong correlations cannot be taken as evidence for cause-and-effect relationships, we interpret our data to indicate that increasing TF disorder likely was an important factor contributing to the evolution of organismic complexity and not merely a concurrent unrelated effect of increasing organismic complexity.Item Identification of Intrinsic Disorder in Complexes from the Protein Data Bank(ACS Publications, 2020-07-14) Zhou, Jianhong; Oldfield, Christopher J.; Yan, Wenying; Shen, Bairong; Dunker, A.Keith; Biochemistry and Molecular Biology, School of MedicineBackground: Intrinsically disordered proteins or regions (IDPs or IDRs) lack stable structures in solution, yet often fold upon binding with partners. IDPs or IDRs are highly abundant in all proteomes and represent a significant modification of sequence → structure → function paradigm. The Protein Data Bank (PDB) includes complexes containing disordered segments bound to globular proteins, but the molecular mechanisms of such binding interactions remain largely unknown. Results: In this study, we present the results of various disorder predictions on a nonredundant set of PDB complexes. In contrast to their structural appearances, many PDB proteins were predicted to be disordered when separated from their binding partners. These predicted-to-be-disordered proteins were observed to form structures depending upon various factors, including heterogroup binding, protein/DNA/RNA binding, disulfide bonds, and ion binding. Conclusions: This study collects many examples of disorder-to-order transition in IDP complex formation, thus revealing the unusual structure–function relationships of IDPs and providing an additional support for the newly proposed paradigm of the sequence → IDP/IDR ensemble → function.Item Improving protein order-disorder classification using charge-hydropathy plots(Springer (Biomed Central Ltd.), 2014) Huang, Fei; Oldfield, Christopher J.; Xue, Bin; Hsu, Wei-Lun; Meng, Jingwei; Liu, Xiaowen; Shen, Li; Romero, Pedro; Uversky, Vladimir N.; Dunker, A. Keith; Department of Biochemistry and Molecular Biology, IU School of MedicineBACKGROUND: The earliest whole protein order/disorder predictor (Uversky et al., Proteins, 41: 415-427 (2000)), herein called the charge-hydropathy (C-H) plot, was originally developed using the Kyte-Doolittle (1982) hydropathy scale (Kyte & Doolittle., J. Mol. Biol, 157: 105-132(1982)). Here the goal is to determine whether the performance of the C-H plot in separating structured and disordered proteins can be improved by using an alternative hydropathy scale. RESULTS: Using the performance of the CH-plot as the metric, we compared 19 alternative hydropathy scales, with the finding that the Guy (1985) hydropathy scale (Guy, Biophys. J, 47:61-70(1985)) was the best of the tested hydropathy scales for separating large collections structured proteins and intrinsically disordered proteins (IDPs) on the C-H plot. Next, we developed a new scale, named IDP-Hydropathy, which further improves the discrimination between structured proteins and IDPs. Applying the C-H plot to a dataset containing 109 IDPs and 563 non-homologous fully structured proteins, the Kyte-Doolittle (1982) hydropathy scale, the Guy (1985) hydropathy scale, and the IDP-Hydropathy scale gave balanced two-state classification accuracies of 79%, 84%, and 90%, respectively, indicating a very substantial overall improvement is obtained by using different hydropathy scales. A correlation study shows that IDP-Hydropathy is strongly correlated with other hydropathy scales, thus suggesting that IDP-Hydropathy probably has only minor contributions from amino acid properties other than hydropathy. CONCLUSION: We suggest that IDP-Hydropathy would likely be the best scale to use for any type of algorithm developed to predict protein disorder.Item Intrinsic Disorder Is a Common Feature of Hub Proteins from Four Eukaryotic Interactomes(PLOS, 2006-08-04) Haynes, Chad; Oldfield, Christopher J.; Ji, Fei; Klitgord, Niels; Cusick, Michael E.; Radivojac, Predrag; Uversky, Vladimir N.; Vidal, Marc; Iakoucheva, Lilia M.; Biochemistry and Molecular Biology, School of MedicineRecent proteome-wide screening approaches have provided a wealth of information about interacting proteins in various organisms. To test for a potential association between protein connectivity and the amount of predicted structural disorder, the disorder propensities of proteins with various numbers of interacting partners from four eukaryotic organisms (Caenorhabditis elegans, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens) were investigated. The results of PONDR VL-XT disorder analysis show that for all four studied organisms, hub proteins, defined here as those that interact with ≥10 partners, are significantly more disordered than end proteins, defined here as those that interact with just one partner. The proportion of predicted disordered residues, the average disorder score, and the number of predicted disordered regions of various lengths were higher overall in hubs than in ends. A binary classification of hubs and ends into ordered and disordered subclasses using the consensus prediction method showed a significant enrichment of wholly disordered proteins and a significant depletion of wholly ordered proteins in hubs relative to ends in worm, fly, and human. The functional annotation of yeast hubs and ends using GO categories and the correlation of these annotations with disorder predictions demonstrate that proteins with regulation, transcription, and development annotations are enriched in disorder, whereas proteins with catalytic activity, transport, and membrane localization annotations are depleted in disorder. The results of this study demonstrate that intrinsic structural disorder is a distinctive and common characteristic of eukaryotic hub proteins, and that disorder may serve as a determinant of protein interactivity.Item Intrinsically disordered domains: Sequence ➔ disorder ➔ function relationships(Wiley, 2019-07-12) Zhou, Jianhong; Oldfield, Christopher J.; Yan, Wenying; Shen, Bairong; Dunker, A. Keith; Biochemistry and Molecular Biology, School of MedicineDisordered domains are long regions of intrinsic disorder that ideally have conserved sequences, conserved disorder, and conserved functions. These domains were first noticed in protein–protein interactions that are distinct from the interactions between two structured domains and the interactions between structured domains and linear motifs or molecular recognition features (MoRFs). So far, disordered domains have not been systematically characterized. Here, we present a bioinformatics investigation of the sequence–disorder–function relationships for a set of probable disordered domains (PDDs) identified from the Pfam database. All the Pfam seed proteins from those domains with at least one PDD sequence were collected. Most often, if a set contains one PDD sequence, then all members of the set are PDDs or nearly so. However, many seed sets have sequence collections that exhibit diverse proportions of predicted disorder and structure, thus giving the completely unexpected result that conserved sequences can vary substantially in predicted disorder and structure. In addition to the induction of structure by binding to protein partners, disordered domains are also induced to form structure by disulfide bond formation, by ion binding, and by complex formation with RNA or DNA. The two new findings, (a) that conserved sequences can vary substantially in their predicted disorder content and (b) that homologues from a single domain can evolve from structure to disorder (or vice versa), enrich our understanding of the sequence ➔ disorder ensemble ➔ function paradigm.