Browsing by Author "Xue, Bin"
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Item 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 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, SCAFFOLDS, AND STOCHASTIC MACHINES(Office of the Vice Chancellor for Research, 2010-04-09) Dunker, A. Keith; Xue, Bin; William, Albert; Uversky, Vladimir N.Scaffold proteins bind additional proteins that then carry out multi-step pathways. How do such machines work? Here a new hypothesis is proposed for the complex consisting of axin, two kinases – GSK3β and CK1α, and β-catenin. The pathway involves four discrete phosphorylations of β-catenin by the two kinases. Like many other scaffold proteins, axin is mostly unstructured [1, 2]. With a length of about 800 residues, axin forms two small domains of less than 100 residues each, and uses only a small number of residues, about 20 per interaction, to bind to GSK3β and β-catenin [1], and presumably also to bind to CK1α. Thus, even with the two domains and 3 partners, axin remains mostly unfolded. The hypothesis is that the unstructured axin molecule holds the three globular proteins in very high local concentrations, like three globules on a rope, and that, by random motions, first CK1α and then GSK3β phosphorylate the disordered tail of β-catenin successively four times. The “conformational changes” of axin that lead to acceleration of phosphorylation are neither specific nor coordinated, but rather are entirely stochastic, with stereochemical fit between the enzymes and their targets leading to the correct ordering of the four phosphorylation steps. In this hypothesis, the scaffold protein acts simply as a flexible tether that leads to acceleration of the multiple steps in the pathway by raising the local concentrations of the key components and by allowing the various components the freedom to collide in various orientations until productive collisions result. Thus, the steps of the pathway are carried out by a stochastic machine. This may be a general mechanism for scaffold-based molecular machines.Item Many-to-one binding by intrinsically disordered protein regions(WORLD SCIENTIFIC, 2019-11-02) Alterovitz, Wei-Lun; Faraggi, Eshel; Oldfield, Christopher J.; Meng, Jingwei; Xue, Bin; Huang, Fei; Romero, Pedro; Kloczkowski, Andrzej; Uversky, Vladimir N.; Dunker, A. Keith; Biochemistry and Molecular Biology, School of MedicineDisordered binding regions (DBRs), which are embedded within intrinsically disordered proteins or regions (IDPs or IDRs), enable IDPs or IDRs to mediate multiple protein-protein interactions. DBR-protein complexes were collected from the Protein Data Bank for which two or more DBRs having different amino acid sequences bind to the same (100% sequence identical) globular protein partner, a type of interaction herein called many-to-one binding. Two distinct binding profiles were identified: independent and overlapping. For the overlapping binding profiles, the distinct DBRs interact by means of almost identical binding sites (herein called “similar”), or the binding sites contain both common and divergent interaction residues (herein called “intersecting”). Further analysis of the sequence and structural differences among these three groups indicate how IDP flexibility allows different segments to adjust to similar, intersecting, and independent binding pockets.Item Protein intrinsic disorder in the acetylome of intracellular and extracellular Toxoplasma gondii(Royal Society of Chemistry, 2013) Xue, Bin; Jeffers, Victoria; Sullivan, William J., Jr.; Uversky, Vladimir N.; Pharmacology and Toxicology, School of MedicineToxoplasma gondii is an obligate intracellular parasite of the phylum Apicomplexa, which includes a number of species of medical and veterinary importance. Inhibitors of lysine deacetylases (KDACs) exhibit potent antiparasitic activity, suggesting that interference with lysine acetylation pathways hold promise for future drug targeting. Using high resolution LC-MS/MS to identify parasite peptides enriched by immunopurification with acetyl-lysine antibody, we recently produced an acetylome of the proliferative intracellular stage of Toxoplasma. In this study, we used similar approaches to greatly expand the Toxoplasma acetylome by identifying acetylated proteins in non-replicating extracellular tachyzoites. The functional breakdown of acetylated proteins in extracellular parasites is similar to intracellular parasites, with an enrichment of proteins involved in metabolism, translation, and chromatin biology. Altogether, we have now detected over 700 acetylation sites on a wide variety of parasite proteins of diverse function in multiple subcellular compartments. We found 96 proteins uniquely acetylated in intracellular parasites, 216 uniquely acetylated in extracellular parasites, and 177 proteins acetylated in both states. Our findings suggest that dramatic changes occur at the proteomic level as tachyzoites transition from the intracellular to extracellular environment, similar to reports documenting significant changes in gene expression during this transition. The expanded dataset also allowed a thorough analysis of the degree of protein intrinsic disorder surrounding lysine residues targeted for this post-translational modification. These analyses indicate that acetylated lysines in proteins from extracellular and intracellular tachyzoites are largely located within similar local environments, and that lysine acetylation preferentially occurs in intrinsically disordered or flexible regions.Item Retro-MoRFs: Identifying Protein Binding Sites by Normal and Reverse Alignment and Intrinsic Disorder Prediction(MDPI, 2010-09-29) Xue, Bin; Dunker, A. Keith; Uversky, Vladimir N.; Biochemistry and Molecular Biology, School of MedicineMany cell functions in all living organisms rely on protein-based molecular recognition involving disorder-to-order transitions upon binding by molecular recognition features (MoRFs). A well accepted computational tool for identifying likely protein-protein interactions is sequence alignment. In this paper, we propose the combination of sequence alignment and disorder prediction as a tool to improve the confidence of identifying MoRF-based protein-protein interactions. The method of reverse sequence alignment is also rationalized here as a novel approach for finding additional interaction regions, leading to the concept of a retro-MoRF, which has the reversed sequence of an identified MoRF. The set of retro-MoRF binding partners likely overlap the partner-sets of the originally identified MoRFs. The high abundance of MoRF-containing intrinsically disordered proteins in nature suggests the possibility that the number of retro-MoRFs could likewise be very high. This hypothesis provides new grounds for exploring the mysteries of protein-protein interaction networks at the genome level.