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Browsing by Subject "Intrinsic Disorder"
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Item 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 MedicineBackground 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.Item Intrinsic Disorder and Protein Evolution: Amino Acid Composition of Proteins in Last Universal AncestorKarne, Sai Harish Babu; Romero, PedroAll twenty amino acids did not appear simultaneously in nature. Instead some of them appeared early, while others were added into the genetic code later. The amino acids that were formed by Miller (1953) are suggested to have appeared early in evolutionary history, and the amino acids associated with codon capture developed late in the course of evolution. The chronological order of appearance of the amino acids proposed by Trifonov (2000) was G/A, V/D, P, S, E/L, T, R, N, K, Q, I, C, H, F, M, Y, W. According to Romero et al. (1997) amino acids G, D, E, P and S are disorder-promoting residues and C, F, W and Y are order-promoting residues this means that the early or the ancient amino acids were disorder promoting and the order promoting residues came late into the genetic code. These observations led to the hypothesis that the first proteins, which were comprised of the early amino acids only, were disordered, and, furthermore, that the appearance of the late amino acids and the appearance of the structural proteins were concurrent. Software developed by Brooks et al. (2004) to find the amino acid composition of the LUA (Last Universal Ancestor) was used to test this hypothesis. For this work, the Clusters of Orhtologous Groups of proteins (65 COGs) were split into enzymes and non-enzymes. It was found that intrinsic disorder was abundant in both the groups of proteins, with non enzymes being much more disorder than enzymes. Further analysis was done to check for the frequency of the modern amino acids C, F, W, and Y in the Protein data bank (PDB) and Swissprot.Item Intrinsic disorder in Viral Proteins Genome-Linked: experimental and predictive analyses(BioMed Central, 2009-02-16) Hébrard, Eugénie; Bessin, Yannick; Michon, Thierry; Longhi, Sonia; Uversky, Vladimir N.; Delalande, François; Van Dorsselaer, Alain; Romero, Pedro; Walter, Jocelyne; Declerck, Nathalie; Fargette, Denis; Biochemistry and Molecular Biology, School of MedicineBackground VPgs are viral proteins linked to the 5' end of some viral genomes. Interactions between several VPgs and eukaryotic translation initiation factors eIF4Es are critical for plant infection. However, VPgs are not restricted to phytoviruses, being also involved in genome replication and protein translation of several animal viruses. To date, structural data are still limited to small picornaviral VPgs. Recently three phytoviral VPgs were shown to be natively unfolded proteins. Results In this paper, we report the bacterial expression, purification and biochemical characterization of two phytoviral VPgs, namely the VPgs of Rice yellow mottle virus (RYMV, genus Sobemovirus) and Lettuce mosaic virus (LMV, genus Potyvirus). Using far-UV circular dichroism and size exclusion chromatography, we show that RYMV and LMV VPgs are predominantly or partly unstructured in solution, respectively. Using several disorder predictors, we show that both proteins are predicted to possess disordered regions. We next extend theses results to 14 VPgs representative of the viral diversity. Disordered regions were predicted in all VPg sequences whatever the genus and the family. Conclusion Based on these results, we propose that intrinsic disorder is a common feature of VPgs. The functional role of intrinsic disorder is discussed in light of the biological roles of VPgs.Item Length-dependent prediction of protein intrinsic disorder(BioMed Central, 2006-04-17) Peng, Kang; Radivojac, Predrag; Vucetic, Slobodan; Dunker, A. Keith; Obradovic, Zoran; Biology, School of ScienceBackground Due to the functional importance of intrinsically disordered proteins or protein regions, prediction of intrinsic protein disorder from amino acid sequence has become an area of active research as witnessed in the 6th experiment on Critical Assessment of Techniques for Protein Structure Prediction (CASP6). Since the initial work by Romero et al. (Identifying disordered regions in proteins from amino acid sequences, IEEE Int. Conf. Neural Netw., 1997), our group has developed several predictors optimized for long disordered regions (>30 residues) with prediction accuracy exceeding 85%. However, these predictors are less successful on short disordered regions (≤30 residues). A probable cause is a length-dependent amino acid compositions and sequence properties of disordered regions. Results We proposed two new predictor models, VSL2-M1 and VSL2-M2, to address this length-dependency problem in prediction of intrinsic protein disorder. These two predictors are similar to the original VSL1 predictor used in the CASP6 experiment. In both models, two specialized predictors were first built and optimized for short (≤30 residues) and long disordered regions (>30 residues), respectively. A meta predictor was then trained to integrate the specialized predictors into the final predictor model. As the 10-fold cross-validation results showed, the VSL2 predictors achieved well-balanced prediction accuracies of 81% on both short and long disordered regions. Comparisons over the VSL2 training dataset via 10-fold cross-validation and a blind-test set of unrelated recent PDB chains indicated that VSL2 predictors were significantly more accurate than several existing predictors of intrinsic protein disorder. Conclusion The VSL2 predictors are applicable to disordered regions of any length and can accurately identify the short disordered regions that are often misclassified by our previous disorder predictors. The success of the VSL2 predictors further confirmed the previously observed differences in amino acid compositions and sequence properties between short and long disordered regions, and justified our approaches for modelling short and long disordered regions separately. The VSL2 predictors are freely accessible for non-commercial use at http://www.ist.temple.edu/disprot/predictorVSL2.phpItem Short Linear Motifs recognized by SH2, SH3 and Ser/Thr Kinase domains are conserved in disordered protein regions(BioMed Central, 2008-09-16) Ren, Siyuan; Uversky, Vladimir N.; Chen, Zhengjun; Dunker, A. Keith; Obradovic, Zoran; Biochemistry and Molecular Biology, School of MedicineBackground Protein interactions are essential for most cellular functions. Interactions mediated by domains that appear in a large number of proteins are of particular interest since they are expected to have an impact on diversities of cellular processes such as signal transduction and immune response. Many well represented domains recognize and bind to primary sequences less than 10 amino acids in length called Short Linear Motifs (SLiMs). Results In this study, we systematically studied the evolutionary conservation of SLiMs recognized by SH2, SH3 and Ser/Thr Kinase domains in both ordered and disordered protein regions. Disordered protein regions are protein sequences that lack a fixed three-dimensional structure under putatively native conditions. We find that, in all these domains examined, SLiMs are more conserved in disordered regions. This trend is more evident in those protein functional groups that are frequently reported to interact with specific domains. Conclusion The correlation between SLiM conservation with disorder prediction demonstrates that functional SLiMs recognized by each domain occur more often in disordered as compared to structured regions of proteins.Item The unfoldomics decade: an update on intrinsically disordered proteins(BioMed Central, 2008-09-16) Dunker, A. Keith; Oldfield, Christopher J.; Meng, Jingwei; Romero, Pedro; Yang, Jack Y.; Walton Chen, Jessica; Vacic, Vladimir; Obradovic, Zoran; Uversky, Vladimir N.; Biochemistry and Molecular Biology, School of MedicineBackground Our first predictor of protein disorder was published just over a decade ago in the Proceedings of the IEEE International Conference on Neural Networks (Romero P, Obradovic Z, Kissinger C, Villafranca JE, Dunker AK (1997) Identifying disordered regions in proteins from amino acid sequence. Proceedings of the IEEE International Conference on Neural Networks, 1: 90–95). By now more than twenty other laboratory groups have joined the efforts to improve the prediction of protein disorder. While the various prediction methodologies used for protein intrinsic disorder resemble those methodologies used for secondary structure prediction, the two types of structures are entirely different. For example, the two structural classes have very different dynamic properties, with the irregular secondary structure class being much less mobile than the disorder class. The prediction of secondary structure has been useful. On the other hand, the prediction of intrinsic disorder has been revolutionary, leading to major modifications of the more than 100 year-old views relating protein structure and function. Experimentalists have been providing evidence over many decades that some proteins lack fixed structure or are disordered (or unfolded) under physiological conditions. In addition, experimentalists are also showing that, for many proteins, their functions depend on the unstructured rather than structured state; such results are in marked contrast to the greater than hundred year old views such as the lock and key hypothesis. Despite extensive data on many important examples, including disease-associated proteins, the importance of disorder for protein function has been largely ignored. Indeed, to our knowledge, current biochemistry books don't present even one acknowledged example of a disorder-dependent function, even though some reports of disorder-dependent functions are more than 50 years old. The results from genome-wide predictions of intrinsic disorder and the results from other bioinformatics studies of intrinsic disorder are demanding attention for these proteins. Results Disorder prediction has been important for showing that the relatively few experimentally characterized examples are members of a very large collection of related disordered proteins that are wide-spread over all three domains of life. Many significant biological functions are now known to depend directly on, or are importantly associated with, the unfolded or partially folded state. Here our goal is to review the key discoveries and to weave these discoveries together to support novel approaches for understanding sequence-function relationships. Conclusion Intrinsically disordered protein is common across the three domains of life, but especially common among the eukaryotic proteomes. Signaling sequences and sites of posttranslational modifications are frequently, or very likely most often, located within regions of intrinsic disorder. Disorder-to-order transitions are coupled with the adoption of different structures with different partners. Also, the flexibility of intrinsic disorder helps different disordered regions to bind to a common binding site on a common partner. Such capacity for binding diversity plays important roles in both protein-protein interaction networks and likely also in gene regulation networks. Such disorder-based signaling is further modulated in multicellular eukaryotes by alternative splicing, for which such splicing events map to regions of disorder much more often than to regions of structure. Associating alternative splicing with disorder rather than structure alleviates theoretical and experimentally observed problems associated with the folding of different length, isomeric amino acid sequences. The combination of disorder and alternative splicing is proposed to provide a mechanism for easily "trying out" different signaling pathways, thereby providing the mechanism for generating signaling diversity and enabling the evolution of cell differentiation and multicellularity. Finally, several recent small molecules of interest as potential drugs have been shown to act by blocking protein-protein interactions based on intrinsic disorder of one of the partners. Study of these examples has led to a new approach for drug discovery, and bioinformatics analysis of the human proteome suggests that various disease-associated proteins are very rich in such disorder-based drug discovery targets.