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Interactions Between The Hepatitis C Virus Non Structural Ns5a Protein And Cellular Signalling Pathways
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Book Synopsis Interactions Between the Hepatitis C Virus Non-structural NS5A Protein and Cellular Signalling Pathways by : Andrew Macdonald
Download or read book Interactions Between the Hepatitis C Virus Non-structural NS5A Protein and Cellular Signalling Pathways written by Andrew Macdonald and published by . This book was released on 2001 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Protein-protein Interactions of the Unstructured Domain II of Hepatitis C Virus NS5A by : Marianne Ngure
Download or read book Protein-protein Interactions of the Unstructured Domain II of Hepatitis C Virus NS5A written by Marianne Ngure and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The hepatitis C virus (HCV) non-structural 5A (NS5A) protein is a multi-functional, RNA binding protein and an essential component of the HCV replication complex. It is subdivided into 3 domains; a highly structured domain I (DI), while DII and DIII are intrinsically unstructured yet mediate crucial interactions with several viral and cellular host factors. NS5A-DII protein mediates the interaction with Cyclophilin A (CypA), a cellular cis/trans isomerase essential for viral replication. Cyclosporine A (CsA), an inhibitor of CypA, inhibits this interaction and suppresses HCV replication. Mutations that confer resistance to CsA and derivatives have been identified within NS5A-DII (D320E and Y321N in Con 1b). These mutations revive HCV replication in vivo, but the underlying mechanism for resistance remains elusive. Using a Förster Resonance Energy Transfer (FRET)-based approach, we determined a slower rate of dissociation of the resistant NS5A-DII complex with CypA, in the presence of CsA. The slow complex dissociation directly correlated with the increasing level of resistance conferred by either single or double mutations within NS5A-DII. By prolonging the protein-protein complex, D320E and Y321N specifically limit the inhibitory effect of CsA on the NS5A-DII complex with CypA, providing a possible biochemical mechanism of resistance to CypA inhibitors. Apart from its CypA binding properties, NS5A-DII also binds RNA, and interacts with the HCV RNA-dependent RNA polymerase NS5B. However, the largely disordered nature of NS5A-DII has limited the characterization of the structure and functional relevance of these interactions. A mass spectrometry (MS)-assisted foot-printing approach provided an in-depth biochemical characterization of the molecular determinants of protein-protein and nucleoprotein interactions of HCV NS5A-DII with CypA, NS5B and RNA. Overlapping but definitive binding sites for each of the three macromolecules were determined. The conserved residue W316 was identified as a principle mediator of protein-protein interaction (CypA and NS5B) while an arginine-rich region of NS5A-DII was crucial for RNA binding. Specifically, NS5A-DII K308 residue was indispensable for RNA-binding. A novel binding site of NS5A-DII on the NS5B polymerase was mapped predominantly to a region associated with RNA binding. Additionally, binding of NS5A-DII diminished the RNA binding and RNA synthesis activity of NS5B polymerase. This implies a potential regulatory function of NS5A-DII on NS5B polymerase activity. Taken together, this work pinpoints key residues in the intrinsically disordered NS5A-DII that necessitate specific viral and host interactions. NS5A-DII has been plucked from obscurity as we begin to understand the biochemical functional relevance for these interactions, and their significance to HCV replication." --
Book Synopsis Virus Versus Body: The Effect of the Hepatitis C Virus NS5A Protein on the Antiviral Response and Cancer Development by :
Download or read book Virus Versus Body: The Effect of the Hepatitis C Virus NS5A Protein on the Antiviral Response and Cancer Development written by and published by . This book was released on 2003 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The Hepatitis C Virus (HCV) non-structural 5A protein (NS5A) has been studied for its ability to increase viral replication rates by repressing the host cell antiviral response and deregulating the host cell-cycle. Recent research conducted with NS5A mutants derived from the HCV replicon system demonstrated NS5A's capacity to repress activation of the IFN-beta promoter. Using luciferase assays, I compared the suppression capabilities of the NS5A mutants 10A and H27 with WT NS5A, revealing that WT NS5A suppresses the IFN-beta promoter more similar to the NS5A 10A mutant than the H27 mutant. I then used cell death assays to demonstrate NS5A's ability to block etoposide-induced cell death. To identify the mechanism by which NS5A is blocking cell death, I used cell death assays comparing cells expressing NS5A with cells lacking expression of the tumor-suppressor protein PKR, revealing that NS5A is must block cell death through interactions with a protein(s) other than PKR.
Book Synopsis Flexible Viruses by : Vladimir Uversky
Download or read book Flexible Viruses written by Vladimir Uversky and published by John Wiley & Sons. This book was released on 2012-02-07 with total page 532 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides up-to-date information on experimental and computational characterization of the structural and functional properties of viral proteins, which are widely involved in regulatory and signaling processes. With chapters by leading research groups, it features current information on the structural and functional roles of intrinsic disorders in viral proteomes. It systematically addresses the measles, HIV, influenza, potato virus, forest virus, bovine virus, hepatitis, and rotavirus as well as viral genomics. After analyzing the unique features of each class of viral proteins, future directions for research and disease management are presented.
Book Synopsis Hepatitis C Virus-host Interactions by : Vanessa Fontanes
Download or read book Hepatitis C Virus-host Interactions written by Vanessa Fontanes and published by . This book was released on 2008 with total page 274 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Functional Interactions of Structural and NS Proteins of Hepatitis C Virus by : Hamed Gouklani
Download or read book Functional Interactions of Structural and NS Proteins of Hepatitis C Virus written by Hamed Gouklani and published by . This book was released on 2011 with total page 362 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hepatitis C virus (HCV) is a small enveloped virus with a positive-sense single stranded RNA genome. Based on its molecular genetic characteristics, the virus has been classified into the Hepacivirus genus of the family Flaviviridae. HCV is one of the major causes of chronic hepatitis which can lead to liver cirrhosis and hepatocellular carcinoma. According to the recent WHO published data, 123 million individuals are infected with HCV (approximately 3% of the world's population) throughout the world. Due to its highly variable nature, HCV is classified into six major genotypes. The HCV genome encodes a single polyprotein that is cleaved to yield at least 10 mature proteins (C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B). The recently developed HCV cell culture system, based on the JFH1 strain of HCV, has provided an opportunity to study the role of the viral proteins in the complete HCV replication cycle in human hepatoma cells. How the viral proteins functionally interact during replication of HCV in cell culture is not completely understood. Passage of cell cultures transfected with HCV genomic RNA containing attenuating mutations allows for the selection of genomes with second site compensatory mutations that restore replication to wild type levels. Using this approach, the functional interactions of p7 and E2 with other viral proteins during HCV replication was investigated.A small protein of 63 amino acids, p7 is encoded at the junction of the structural and non-strucutural region. p7 is a highly hydrophobic, integral membrane protein and is classified in the viroporin family. In this thesis, it is shown that p7 is critical for production of viral particles and is implicated in a late step of particle assembly. Since the protein plays a critical role in the virus life cycle, chemical compounds that block p7 function are potential candidates for anti-viral therapy. In this thesis, a chimeric JFH1 genome that encodes the p7 protein of genotype (GT) 1b strain J4 was generated. The intergenotypic chimeric genome was nonviable in human hepatoma cells and infectious chimeric virions were only produced after cells harboring the chimeric genomes were passaged several times. To investigate the emergence of compensatory mutations in the viral proteins during cell passaging, the consensus sequences of the entire polyprotein coding regions of the wild type JFH1 and three chimeric viruses were determined. Sequence analysis revealed mutations in core, NS2, NS5A and NS5B. Reverse genetic analysis demonstrated that any one of the single mutations restored the infectivity of the defective chimeric genomes. These data suggest that there are critical genetic interactions between p7 with core, NS2, NS5A and NS5B. In addition, a stable physical interaction between p7 and NS2 is shown in a transient expression system. The HCV glycoproteins E1 and E2 are present on the surface of virions as a heterodimer that attach virions to host cell receptors and facilitate virus fusion and entry. HCV entry proceeds via attachment to glycosaminoglycans followed by binding to scavenger receptor type B class I, and the tetraspanin CD81. Recently, claudin-1 and occludin have emerged as additional receptors required for entry. E2 has a receptor binding domain (E2661RBD) that conatins three variable regions, hypervariable regions 1 (HVR1), HVR2 and the intergenotypic variable region (igVR). In this thesis, HVR1 of E2 was deleted in the context of full-length replication comptetent HCV. Deletion of HVR1 increases CD81-binding ability of the mutant and also increases its susceptibility to neutralizing antibody MAb 24. The infectivity of the HVR1 deleted virions was attenuated approximately 10-fold prior to accumulation of compensatory mutations. Sequencing of cDNA obtained from reverted virions revealed mutations in E1 (I262L) and E2 (N415D). Reverse genetic studies revealed that I262L improved the infectivity of HVR1 deleted virions 2.5 fold while N415D restored infectivity to wild type levels. These data suggest that mutations within E1 or E2 can compensate for the reduction in infectivity observed for HVR1 deleted viruses.In summary, this thesis demonstrates the importance of functional interactions between HCV proteins during virus morphogenesis and infectivity.
Book Synopsis Hepatitis C Virus Nonstructural Protein 5A by : Taeyo Chestley
Download or read book Hepatitis C Virus Nonstructural Protein 5A written by Taeyo Chestley and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hepatitis C virus (HCV) is a hepatotropic pathogen present in approximately 2.8% of the population with 3-4 million new infections every year. Up to 85% of infections progress to a chronic disease associated with development of steatosis, cirrhosis and hepatocellular carcinoma. Viral protein, Nonstructural 5A (NS5A), has eluded a defined role in the HCV life cycle despite being essential to viral propagation and host cell modulation. NS5A is a phosphoprotein appearing as two molecular weight proteoforms by SDS-PAGE referred to as the basally phosphorylated and hyperphosphorylated forms. Different NS5A phospho-proteoforms may direct its function acting as a molecular switch between replication and assembly. Two aspects of NS5A biology were addressed: 1) NS5A host cell protein-protein interactions and 2) defining phosphorylation sites on NS5A. To identify NS5A-host protein-protein interactions, a novel tandem affinity purification (TAP) technique was implemented. A HBH (histidine-biotin-histidine) tag was affixed to NS5A-2a (JFH1) and cells were generated stably expressing this construct. Tagged proteins were purified using native-state (nTAP) and cross-linked, denaturing (xdTAP) using immobilized metal chelate and streptavidin resins. Purified samples were subjected to tandem-mass spectrometry and database searching to generate an NS5A interacting protein list. Co-immunoprecipitation and colocalization confirmed host cell Cell Cycle and Apoptosis Regulator protein 2 (CCAR2) as an NS5A interacting protein. Phosphorylation analysis used NS5A isolated as a tagged protein, part of a subgenomic (SG) replicon, or a tagged protein within a SG replicon. Subsequent tandem mass spectrometry allowed for identification of 28 phosphorylation sites, 20 of which were novel. Phosphoablatant and phosphomimetic mutation of the phosphoacceptor sites were used to evaluate the impact of phosphorylating these residues to the JFH1 virus. While majority of these mutations had no impact, T204D, T210A/D, S225D, S229A/D, S232A/D, S235A/D, S238A/D, T334A/D, and T363A/D mutants were reduced in their replicative capacity. NS5A phospho-proteoform ratios were evaluated with S151D, S225A and S232A mutants primarily basally phosphorylated while T213D, T210A/D were mainly hyperphosphorylated. Mutants T210D, S229A, S229D, and S235A failed to produce virus. A novel observation was made that NS5A is principally hyperphosphorylated at early time-points post RNA electroporation but past 72 hours the basally phosphorylated form predominates.
Book Synopsis Investigation Into Hepatitis C Non-structural Protein 3 and Its Role in Hepatocellular Carcinoma by : Chelsey D. Pankiw
Download or read book Investigation Into Hepatitis C Non-structural Protein 3 and Its Role in Hepatocellular Carcinoma written by Chelsey D. Pankiw and published by . This book was released on 2007 with total page 89 pages. Available in PDF, EPUB and Kindle. Book excerpt: Infection with Hepatitis C Virus (HCV) often becomes chronic and can lead to cellular transformation and ultimately hepatocellular carcinoma in 5% of individuals infected. This phenomenon triggers considerable interest in the analysis of potential interactions between individual HCV proteins and host cell proteins regulating cell growth. Recently, the potential of NS3 protease to elicit a malignant response has been mildly explored. Viral proteases are known to affect cellular metabolism. Without regulatory restrictions, NS3 has the ability to not only disrupt growth pathways by direct protein-protein interaction, but also to degrade regulatory proteins, thereby influencing the initial stages of cellular transformation. It was found that expression of NS3 in Huh 7.0 cells could activate several oncogene - related pathways namely NFkB and c-fos. Detection was measured via chemiluminescence and mammalian two hybrid assays. I have currently narrowed down the region of NS3 responsible for this up-regulation to approx. 300 amino acids. Identification of this motif will not only provide powerful insight into the host factors involved in HCV protein interaction but will ultimately serve to provide therapeutic potential in treatment of hepatocellular carcinoma.
Book Synopsis Functional Analysis of Domain I of the Hepatitis C Virus Non-structural NS5A Protein by : Chunhong Yin
Download or read book Functional Analysis of Domain I of the Hepatitis C Virus Non-structural NS5A Protein written by Chunhong Yin and published by . This book was released on 2018 with total page 230 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Viral Proteases and Their Inhibitors by : Satya Prakash Gupta
Download or read book Viral Proteases and Their Inhibitors written by Satya Prakash Gupta and published by Academic Press. This book was released on 2017-07-03 with total page 518 pages. Available in PDF, EPUB and Kindle. Book excerpt: Viral Proteases and Their Inhibitors provides a thorough examination of viral proteases from their molecular components, to therapeutic applications. As information on three dimensional structures and biological functions of these viral proteases become known, unexpected protein folds and unique mechanisms of proteolysis are realized. This book investigates how this facilitates the design and development of potent antiviral agents used against life-threatening viruses. Users will find descriptions of each virus that detail the structure and function of viral proteases, discuss the design and development of inhibitors, and analyze the structure-activity relationships of inhibitors. This book is ideal biochemists, virologists and those working on antiviral agents. Provides comprehensive, state-of-the-art coverage of virus infections, the virus lifecycle, and mechanisms of protease inhibition Analyzes structure-activity relationships of inhibitors of each viral protease Presents an in-depth view of the structure and function of viral proteases
Download or read book The Liver written by Irwin M. Arias and published by John Wiley & Sons. This book was released on 2020-03-09 with total page 1156 pages. Available in PDF, EPUB and Kindle. Book excerpt: Bridging the gap between basic scientific advances and the understanding of liver disease — the extensively revised new edition of the premier text in the field. The latest edition of The Liver: Biology and Pathobiology remains a definitive volume in the field of hepatology, relating advances in biomedical sciences and engineering to understanding of liver structure, function, and disease pathology and treatment. Contributions from leading researchers examine the cell biology of the liver, the pathobiology of liver disease, the liver’s growth, regeneration, metabolic functions, and more. Now in its sixth edition, this classic text has been exhaustively revised to reflect new discoveries in biology and their influence on diagnosing, managing, and preventing liver disease. Seventy new chapters — including substantial original sections on liver cancer and groundbreaking advances that will have significant impact on hepatology — provide comprehensive, fully up-to-date coverage of both the current state and future direction of hepatology. Topics include liver RNA structure and function, gene editing, single-cell and single-molecule genomic analyses, the molecular biology of hepatitis, drug interactions and engineered drug design, and liver disease mechanisms and therapies. Edited by globally-recognized experts in the field, this authoritative volume: Relates molecular physiology to understanding disease pathology and treatment Links the science and pathology of the liver to practical clinical applications Features 16 new “Horizons” chapters that explore new and emerging science and technology Includes plentiful full-color illustrations and figures The Liver: Biology and Pathobiology, Sixth Edition is an indispensable resource for practicing and trainee hepatologists, gastroenterologists, hepatobiliary and liver transplant surgeons, and researchers and scientists in areas including hepatology, cell and molecular biology, virology, and drug metabolism.
Book Synopsis Characterization of the Interactions Between Cellular Proteins and Hepatitis C Virus Core Protein by : Tsai-Yuan Hsieh
Download or read book Characterization of the Interactions Between Cellular Proteins and Hepatitis C Virus Core Protein written by Tsai-Yuan Hsieh and published by . This book was released on 1998 with total page 264 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Translation In Eukaryotes by : Hans Trachsel
Download or read book Translation In Eukaryotes written by Hans Trachsel and published by CRC Press. This book was released on 1991-07-24 with total page 438 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents an up-to-date review of the mechanisms and regulation of translation in eukaryotes. Topics covered include the basic biochemical reactions of translation initiation, elongation and termination, and the regulation of these reactions under different physiological conditions and in virus-infected cells. The book belongs on the shelf of everyone interested in translation in eukaryotes, including students and researchers requiring comprehensive overviews of most aspects of translation and instructors who want to cover these topics at an advanced level.
Book Synopsis Liver Disease in Children by : Frederick J. Suchy
Download or read book Liver Disease in Children written by Frederick J. Suchy and published by Cambridge University Press. This book was released on 2021-03-18 with total page 875 pages. Available in PDF, EPUB and Kindle. Book excerpt: Liver disease in children is increasing in prevalence, placing a huge burden on healthcare systems and often requiring long-term management. Offering an integrative approach to the science and clinical practice of pediatric hepatology, this is the definitive reference text for improved diagnosis and treatment strategies. In the new edition of this authoritative text, chapters have been thoroughly revised in line with major advances in the field, such as recognizing the increased frequency of fatty liver disease, and how genetic testing has the potential to establish earlier diagnoses for a variety of diseases. Disorders covered include cholestasis, metabolic disorders and hepatitis, with their presentation across the spectrum of infancy, childhood and adolescence discussed. The indications and surgical aspects of liver transplant are explained and post-transplant care is described in detail. This is a valuable resource for pediatricians, hepatologists, gastroenterologists and all clinicians involved in the care of children with liver diseases.
Book Synopsis Molecular Virology of Human Pathogenic Viruses by : Wang-Shick Ryu
Download or read book Molecular Virology of Human Pathogenic Viruses written by Wang-Shick Ryu and published by Academic Press. This book was released on 2016-03-30 with total page 441 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular Virology of Human Pathogenic Viruses presents robust coverage of the key principles of molecular virology while emphasizing virus family structure and providing key context points for topical advances in the field. The book is organized in a logical manner to aid in student discoverability and comprehension and is based on the author’s more than 20 years of teaching experience. Each chapter will describe the viral life cycle covering the order of classification, virion and genome structure, viral proteins, life cycle, and the effect on host and an emphasis on virus-host interaction is conveyed throughout the text. Molecular Virology of Human Pathogenic Viruses provides essential information for students and professionals in virology, molecular biology, microbiology, infectious disease, and immunology and contains outstanding features such as study questions and recommended journal articles with perspectives at the end of each chapter to assist students with scientific inquiries and in reading primary literature. Presents viruses within their family structure Contains recommended journal articles with perspectives to put primary literature in context Includes integrated recommended reading references within each chapter Provides access to online ancillary package inclusive of annotated PowerPoint images, instructor’s manual, study guide, and test bank
Book Synopsis Viral Polymerases by : Satya Prakash Gupta
Download or read book Viral Polymerases written by Satya Prakash Gupta and published by Academic Press. This book was released on 2018-10-29 with total page 498 pages. Available in PDF, EPUB and Kindle. Book excerpt: Viral Polymerases: Structures, Functions and Roles as Antiviral Drug Targets presents in-depth study information on the structure and functions of polymerases and their roles in the lifecycle of viruses, and as drug targets. Viral polymerases constitute a vital component in the lifecycle of many viruses, such as human immunodeficiency virus (HIV), hepatitis viruses, influenza virus, and several others. They are essentially required for the replication of viruses. Thus, the polymerases that can be found in viruses (called viral polymerases) represent favorable targets for the design and development of antiviral drugs. Provides comprehensive, state-of-the-art coverage on virus infections, the virus lifecycle, and mechanisms of polymerase inhibition Analyzes the structure-activity relationships of inhibitors of each viral polymerase Presents a consistent and comprehensive coverage of all aspects of viral polymerases, including structure, function and their role as antiviral drug targets
Book Synopsis Human Tumor Viruses by : Dennis J. McCance
Download or read book Human Tumor Viruses written by Dennis J. McCance and published by . This book was released on 1998 with total page 382 pages. Available in PDF, EPUB and Kindle. Book excerpt: This valuable new book describes the molecular biology and pathogenesis of certain viruses linked with human cancers. It provides an up–to–date account of the progress in our knowledge of the virus/host interactions which lead to cancer, as well as insights on the complexity of virus/host interactions in general, most of which have yet to be delineated. The volume also offers an historical perspective of cancer viruses as well as an examination of the geographical distribution and prevalence of cancers. Human Tumor Viruses is essential reading for researchers and graduate students in virology, cell biology, pathology, and oncology and for anyone engaged in cancer research.
