| Structural highlights
Function
POLG_HCVCO Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity).[1] [2] E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity).[3] [4] P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity (By similarity).[5] [6] Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity).[7] [8] NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand. Cleaves the host antiviral protein MAVS (By similarity). NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state.[9] [10] NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity).[11] [12] NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity).[13] [14] NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).[15] [16]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Hepatitis C virus (HCV) is a human pathogen affecting nearly 3% of the world's population. Chronic infections can lead to cirrhosis and liver cancer. The RNA replication machine of HCV is a multi-subunit membrane-associated complex. The non-structural protein NS5A is an active component of HCV replicase, as well as a pivotal regulator of replication and a modulator of cellular processes ranging from innate immunity to dysregulated cell growth. NS5A is a large phosphoprotein (56-58 kDa) with an amphipathic alpha-helix at its amino terminus that promotes membrane association. After this helix region, NS5A is organized into three domains. The N-terminal domain (domain I) coordinates a single zinc atom per protein molecule. Mutations disrupting either the membrane anchor or zinc binding of NS5A are lethal for RNA replication. However, probing the role of NS5A in replication has been hampered by a lack of structural information about this multifunctional protein. Here we report the structure of NS5A domain I at 2.5-A resolution, which contains a novel fold, a new zinc-coordination motif and a disulphide bond. We use molecular surface analysis to suggest the location of protein-, RNA- and membrane-interaction sites.
Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase.,Tellinghuisen TL, Marcotrigiano J, Rice CM Nature. 2005 May 19;435(7040):374-9. PMID:15902263[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8. Epub 2003 Apr 17. PMID:12702807 doi:http://dx.doi.org/10.1126/science.1082604
- ↑ Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S, Bartholomew L, De Francesco R. Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol. 2004 Dec;78(23):13306-14. PMID:15542681 doi:http://dx.doi.org/10.1128/JVI.78.23.13306-13314.2004
- ↑ Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8. Epub 2003 Apr 17. PMID:12702807 doi:http://dx.doi.org/10.1126/science.1082604
- ↑ Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S, Bartholomew L, De Francesco R. Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol. 2004 Dec;78(23):13306-14. PMID:15542681 doi:http://dx.doi.org/10.1128/JVI.78.23.13306-13314.2004
- ↑ Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8. Epub 2003 Apr 17. PMID:12702807 doi:http://dx.doi.org/10.1126/science.1082604
- ↑ Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S, Bartholomew L, De Francesco R. Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol. 2004 Dec;78(23):13306-14. PMID:15542681 doi:http://dx.doi.org/10.1128/JVI.78.23.13306-13314.2004
- ↑ Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8. Epub 2003 Apr 17. PMID:12702807 doi:http://dx.doi.org/10.1126/science.1082604
- ↑ Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S, Bartholomew L, De Francesco R. Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol. 2004 Dec;78(23):13306-14. PMID:15542681 doi:http://dx.doi.org/10.1128/JVI.78.23.13306-13314.2004
- ↑ Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8. Epub 2003 Apr 17. PMID:12702807 doi:http://dx.doi.org/10.1126/science.1082604
- ↑ Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S, Bartholomew L, De Francesco R. Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol. 2004 Dec;78(23):13306-14. PMID:15542681 doi:http://dx.doi.org/10.1128/JVI.78.23.13306-13314.2004
- ↑ Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8. Epub 2003 Apr 17. PMID:12702807 doi:http://dx.doi.org/10.1126/science.1082604
- ↑ Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S, Bartholomew L, De Francesco R. Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol. 2004 Dec;78(23):13306-14. PMID:15542681 doi:http://dx.doi.org/10.1128/JVI.78.23.13306-13314.2004
- ↑ Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8. Epub 2003 Apr 17. PMID:12702807 doi:http://dx.doi.org/10.1126/science.1082604
- ↑ Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S, Bartholomew L, De Francesco R. Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol. 2004 Dec;78(23):13306-14. PMID:15542681 doi:http://dx.doi.org/10.1128/JVI.78.23.13306-13314.2004
- ↑ Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8. Epub 2003 Apr 17. PMID:12702807 doi:http://dx.doi.org/10.1126/science.1082604
- ↑ Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S, Bartholomew L, De Francesco R. Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol. 2004 Dec;78(23):13306-14. PMID:15542681 doi:http://dx.doi.org/10.1128/JVI.78.23.13306-13314.2004
- ↑ Tellinghuisen TL, Marcotrigiano J, Rice CM. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature. 2005 May 19;435(7040):374-9. PMID:15902263 doi:10.1038/nature03580
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