IU Indianapolis ScholarWorks :: Browsing by Author "Uversky, Vladimir N."

Browsing by Author "Uversky, Vladimir N."

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A Comparative Experimental and Computational Study on the Nature of the Pangolin-CoV and COVID-19 Omicron
(MDPI, 2024-07-09) Wei, Lai; Song, Lihua; Dunker, A. Keith; Foster, James A.; Uversky, Vladimir N.; Goh, Gerard Kian-Meng; Biochemistry and Molecular Biology, School of Medicine
The relationship between pangolin-CoV and SARS-CoV-2 has been a subject of debate. Further evidence of a special relationship between the two viruses can be found by the fact that all known COVID-19 viruses have an abnormally hard outer shell (low M disorder, i.e., low content of intrinsically disordered residues in the membrane (M) protein) that so far has been found in CoVs associated with burrowing animals, such as rabbits and pangolins, in which transmission involves virus remaining in buried feces for a long time. While a hard outer shell is necessary for viral survival, a harder inner shell could also help. For this reason, the N disorder range of pangolin-CoVs, not bat-CoVs, more closely matches that of SARS-CoV-2, especially when Omicron is included. The low N disorder (i.e., low content of intrinsically disordered residues in the nucleocapsid (N) protein), first observed in pangolin-CoV-2017 and later in Omicron, is associated with attenuation according to the Shell-Disorder Model. Our experimental study revealed that pangolin-CoV-2017 and SARS-CoV-2 Omicron (XBB.1.16 subvariant) show similar attenuations with respect to viral growth and plaque formation. Subtle differences have been observed that are consistent with disorder-centric computational analysis.
A Study on the Nature of SARS-CoV-2 Using the Shell Disorder Models: Reproducibility, Evolution, Spread, and Attenuation
(MDPI, 2022-09-23) Goh, Gerard Kian-Meng; Dunker, A. Keith; Foster, James A.; Uversky, Vladimir N.; Biochemistry and Molecular Biology, School of Medicine
The basic tenets of the shell disorder model (SDM) as applied to COVID-19 are that the harder outer shell of the virus shell (lower PID-percentage of intrinsic disorder-of the membrane protein M, PIDM) and higher flexibility of the inner shell (higher PID of the nucleocapsid protein N, PIDN) are correlated with the contagiousness and virulence, respectively. M protects the virion from the anti-microbial enzymes in the saliva and mucus. N disorder is associated with the rapid replication of the virus. SDM predictions are supported by two experimental observations. The first observation demonstrated lesser and greater presence of the Omicron particles in the lungs and bronchial tissues, respectively, as there is a greater level of mucus in the bronchi. The other observation revealed that there are lower viral loads in 2017-pangolin-CoV, which is predicted to have similarly low PIDN as Omicron. The abnormally hard M, which is very rarely seen in coronaviruses, arose from the fecal-oral behaviors of pangolins via exposure to buried feces. Pangolins provide an environment for coronavirus (CoV) attenuation, which is seen in Omicron. Phylogenetic study using M shows that COVID-19-related bat-CoVs from Laos and Omicron are clustered in close proximity to pangolin-CoVs, which suggests the recurrence of interspecies transmissions. Hard M may have implications for long COVID-19, with immune systems having difficulty degrading viral proteins/particles.
Characterization of intrinsically disordered proteins with electrospray ionization mass spectrometry: conformational heterogeneity of alpha-synuclein
(Wiley, 2010-02-15) Frimpong, Agya K.; Abzalimov, Rinat R.; Uversky, Vladimir N.; Kaltashov, Igor A.; Medicine, School of Medicine
Conformational heterogeneity of alpha-synuclein was studied with electrospray ionization mass spectrometry by analyzing protein ion charge state distributions, where the extent of multiple charging reflects compactness of the protein conformations in solution. Although alpha-synuclein lacks a single well-defined structure under physiological conditions, it was found to sample four distinct conformational states, ranging from a highly structured one to a random coil. The compact highly structured state of alpha-synuclein is present across the entire range of conditions tested (pH ranging from 2.5 to 10, alcohol content from 0% to 60%), but is particularly abundant in acidic solutions. The only other protein state populated in acidic solutions is a partially folded intermediate state lacking stable tertiary structure. Another, more compact intermediate state is induced by significant amounts of ethanol used as a co-solvent and appears to represent a partially folded conformation with high beta-sheet content. Protein dimerization is observed throughout the entire range of conditions tested, although only acidic solutions favor formation of highly structured dimers of alpha-synuclein. These dimers are likely to present the earliest stages in protein aggregation leading to globular oligomers and, subsequently, protofibrils
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 Medicine
Composition Profiler: a tool for discovery and visualization of amino acid composition differences
(BioMed Central, 2007-06-19) Vacic, Vladimir; Uversky, Vladimir N.; Dunker, A. Keith; Lonardi, Stefano; Biochemistry and Molecular Biology, School of Medicine
Background Composition Profiler is a web-based tool for semi-automatic discovery of enrichment or depletion of amino acids, either individually or grouped by their physico-chemical or structural properties. Results The program takes two samples of amino acids as input: a query sample and a reference sample. The latter provides a suitable background amino acid distribution, and should be chosen according to the nature of the query sample, for example, a standard protein database (e.g. SwissProt, PDB), a representative sample of proteins from the organism under study, or a group of proteins with a contrasting functional annotation. The results of the analysis of amino acid composition differences are summarized in textual and graphical form. Conclusion As an exploratory data mining tool, our software can be used to guide feature selection for protein function or structure predictors. For classes of proteins with significant differences in frequencies of amino acids having particular physico-chemical (e.g. hydrophobicity or charge) or structural (e.g. α helix propensity) properties, Composition Profiler can be used as a rough, light-weight visual classifier.
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 Medicine
Intrinsic 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.
D2P2: database of disordered protein predictions
(Oxford University Press, 2013) Oates, Matt E.; Romero, Pedro; Ishida, Takashi; Ghalwash, Mohamed; Mizianty, Marcin J.; Xue, Bin; Dosztányi, Zsuzsanna; Uversky, Vladimir N.; Obradovic, Zoran; Kurgan, Lukasz; Dunker, A. Keith; Gough, Julian; Center for Computational Biology and Bioinformatics, School of Medicine
We present the Database of Disordered Protein Prediction (D(2)P(2)), available at http://d2p2.pro (including website source code). A battery of disorder predictors and their variants, VL-XT, VSL2b, PrDOS, PV2, Espritz and IUPred, were run on all protein sequences from 1765 complete proteomes (to be updated as more genomes are completed). Integrated with these results are all of the predicted (mostly structured) SCOP domains using the SUPERFAMILY predictor. These disorder/structure annotations together enable comparison of the disorder predictors with each other and examination of the overlap between disordered predictions and SCOP domains on a large scale. D(2)P(2) will increase our understanding of the interplay between disorder and structure, the genomic distribution of disorder, and its evolutionary history. The parsed data are made available in a unified format for download as flat files or SQL tables either by genome, by predictor, or for the complete set. An interactive website provides a graphical view of each protein annotated with the SCOP domains and disordered regions from all predictors overlaid (or shown as a consensus). There are statistics and tools for browsing and comparing genomes and their disorder within the context of their position on the tree of life.
Disease-Associated Mutations Disrupt Functionally Important Regions of Intrinsic Protein Disorder
(Public Library of Science, 2012) Vacic, Vladimir; Markwick, Phineus R. L.; Oldfield, Christopher J.; Zhao, Xiaoyue; Haynes, Chad; Uversky, Vladimir N.; Iakoucheva, Lilia M.; Biochemistry and Molecular Biology, School of Medicine
The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations.
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 Medicine
The 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.
Effects of Various Flavonoids on the -Synuclein Fibrillation Process
(Hindawi, 2010-01-28) Meng, Xiaoyun; Munishkina, Larissa A.; Fink, Anthony L.; Uversky, Vladimir N.
α-Synuclein aggregation and fibrillation are closely associated with the formation of Lewy bodies in neurons and are implicated in the causative pathogenesis of Parkinson's disease and other synucleinopathies. Currently, there is no approved therapeutic agent directed toward preventing the protein aggregation, which has been recently shown to have a key role in the cytotoxic nature of amyloidogenic proteins. Flavonoids, known as plant pigments, belong to a broad family of polyphenolic compounds. Over 4,000 flavonoids have been identified from various plants and foodstuffs derived from plants and have been demonstrated as potential neuroprotective agents. In this study 48 flavonoids belonging to several classes with structures differing in the position of double bonds and ring substituents were tested for their ability to inhibit the fibrillation of α-synuclein in vitro. A variety of flavonoids inhibited α-synuclein fibrillation, and most of the strong inhibitory flavonoids were also found to disaggregate preformed fibrils.

Browsing by Author "Uversky, Vladimir N."

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