Browsing by Subject "Intrinsically disordered proteins"

Now showing 1 - 7 of 7
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    Characterization of intrinsically disordered regions in proteins informed by human genetic diversity
    (PLOS, 2022-03-11) Ahmed, Shehab S.; Rifat, Zaara T.; Lohia, Ruchi; Campbell, Arthur J.; Dunker, A. Keith; Rahman, M. Sohel; Iqbal, Sumaiya; Biochemistry and Molecular Biology, School of Medicine
    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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    DisProt: intrinsic protein disorder annotation in 2020
    (Oxford University Press, 2020-01-08) Hatos, András; Hajdu-Soltész, Borbála; Monzon, Alexander M.; Palopoli, Nicolas; Álvarez, Lucía; Aykac-Fas, Burcu; Bassot, Claudio; Benítez, Guillermo I.; Bevilacqua, Martina; Chasapi, Anastasia; Chemes, Lucia; Davey, Norman E.; Davidović, Radoslav; Dunker, A. Keith; Elofsson, Arne; Gobeill, Julien; González Foutel, Nicolás S.; Sudha, Govindarajan; Guharoy, Mainak; Horvath, Tamas; Iglesias, Valentin; Kajava, Andrey V.; Kovacs, Orsolya P.; Lamb, John; Lambrughi, Matteo; Lazar, Tamas; Leclercq, Jeremy Y.; Leonardi, Emanuela; Macedo-Ribeiro, Sandra; Macossay-Castillo, Mauricio; Maiani, Emiliano; Manso, José A.; Marino-Buslje, Cristina; Martínez-Pérez, Elizabeth; Mészáros, Bálint; Mičetić, Ivan; Minervini, Giovanni; Murvai, Nikoletta; Necci, Marco; Ouzounis, Christos A.; Pajkos, Mátyás; Paladin, Lisanna; Pancsa, Rita; Papaleo, Elena; Parisi, Gustavo; Pasche, Emilie; Barbosa Pereira, Pedro J.; Promponas, Vasilis J.; Pujols, Jordi; Quaglia, Federica; Ruch, Patrick; Salvatore, Marco; Schad, Eva; Szabo, Beata; Szaniszló, Tamás; Tamana, Stella; Tantos, Agnes; Veljkovic, Nevena; Ventura, Salvador; Vranken, Wim; Dosztányi, Zsuzsanna; Tompa, Peter; Tosatto, Silvio C. E.; Piovesan, Damiano; Medicine, School of Medicine
    The Database of Protein Disorder (DisProt, URL: https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the ‘dark’ proteome.
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    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 Medicine
    Background: 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.
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    Intrinsically disordered proteins in molecular recognition and structural proteomics
    (2014-05) Oldfield, Christopher John; Janga, Sarath Chandra; Dunker, A. Keith; Shen, Li; Xia, Yuni; Uversky, Vladimir N.
    Intrinsically disordered proteins (IDPs) are abundant in nature, being more prevalent in the proteomes of eukaryotes than those of bacteria or archaea. As introduced in Chapter I, these proteins, or portions of these proteins, lack stable equilibrium structures and instead have dynamic conformations that vary over time and population. Despite the lack of preformed structure, IDPs carry out many and varied molecular functions and participate in vital biological pathways. In particular, IDPs play important roles in cellular signaling that is, in part, enabled by the ability of IDPs to mediate molecular recognition. In Chapter II, the role of intrinsic disorder in molecular recognition is examined through two example IDPs: p53 and 14-3-3. The p53 protein uses intrinsically disordered regions at its N- and C-termini to interact with a large number of partners, often using the same residues. The 14-3-3 protein is a structured domain that uses the same binding site to recognize multiple intrinsically disordered partners. Examination of the structural details of these interactions highlights the importance of intrinsic disorder and induced fit in molecular recognition. More generally, many intrinsically disordered regions that mediate interactions share similar features that are identifiable from protein sequence. Chapter IV reviews several models of IDP mediated protein-protein interactions that use completely different parameterizations. Each model has its relative strengths in identifying novel interaction regions, and all suggest that IDP mediated interactions are common in nature. In addition to the biologic importance of IDPs, they are also practically important in the structural study of proteins. The presence of intrinsic disordered regions can inhibit crystallization and solution NMR studies of otherwise well-structured proteins. This problem is compounded in the context of high throughput structure determination. In Chapter III, the effect of IDPs on structure determination by X-ray crystallography is examined. It is found that protein crystals are intolerant of intrinsic disorder by examining existing crystal structures from the PDB. A retrospective analysis of Protein Structure Initiative data indicates that prediction of intrinsic disorder may be useful in the prioritization and improvement of targets for structure determination.
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    On the roles of intrinsically disordered proteins and regions in cell communication and signaling
    (BMC, 2021-08-30) Bondos, Sarah E.; Dunker, A. Keith; Uversky, Vladimir N.; Biochemistry and Molecular Biology, School of Medicine
    For 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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    Optimizing hydropathy scale to improve IDP prediction and characterizing IDPs' functions
    (2014-01) Huang, Fei; Dunker, A. Keith; Chen, Jake; Hurley, Thomas D., 1961-; Shen, Li
    Intrinsically disordered proteins (IDPs) are flexible proteins without defined 3D structures. Studies show that IDPs are abundant in nature and actively involved in numerous biological processes. Two crucial subjects in the study of IDPs lie in analyzing IDPs’ functions and identifying them. We thus carried out three projects to better understand IDPs. In the 1st project, we propose a method that separates IDPs into different function groups. We used the approach of CH-CDF plot, which is based the combined use of two predictors and subclassifies proteins into 4 groups: structured, mixed, disordered, and rare. Studies show different structural biases for each group. The mixed class has more order-promoting residues and more ordered regions than the disordered class. In addition, the disordered class is highly active in mitosis-related processes among others. Meanwhile, the mixed class is highly associated with signaling pathways, where having both ordered and disordered regions could possibly be important. The 2nd project is about identifying if an unknown protein is entirely disordered. One of the earliest predictors for this purpose, the charge-hydropathy plot (C-H plot), exploited the charge and hydropathy features of the protein. Not only is this algorithm simple yet powerful, its input parameters, charge and hydropathy, are informative and readily interpretable. We found that using different hydropathy scales significantly affects the prediction accuracy. Therefore, we sought to identify a new hydropathy scale that optimizes the prediction. This new scale achieves an accuracy of 91%, a significant improvement over the original 79%. In our 3rd project, we developed a per-residue C-H IDP predictor, in which three hydropathy scales are optimized individually. This is to account for the amino acid composition differences in three regions of a protein sequence (N, C terminus and internal). We then combined them into a single per-residue predictor that achieves an accuracy of 74% for per-residue predictions for proteins containing long IDP regions.
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    Per Aspera ad Chaos: Vladimir Uversky’s Odyssey through the Strange World of Intrinsically Disordered Proteins
    (MDPI, 2023-06-19) Kulkarni, Prakash; Brocca, Stefania; Dunker, A. Keith; Longhi, Sonia; Biochemistry and Molecular Biology, School of Medicine