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O92532

- POLG_HCVVP

UniProt

O92532 - POLG_HCVVP

Protein

Genome polyprotein

Gene
N/A
Organism
Hepatitis C virus genotype 6h (isolate VN004) (HCV)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 114 (01 Oct 2014)
      Sequence version 3 (23 Jan 2007)
      Previous versions | rss
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    Functioni

    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.By similarity
    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 are 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.By similarity
    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.By similarity
    Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation By similarity.By similarity
    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/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. 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 and inhibits the host antiviral protein MAVS By similarity.By similarity
    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.By similarity
    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.By similarity
    NS5B is an RNA-dependent RNA polymerase that plays an essential role in the virus replication.By similarity

    Catalytic activityi

    Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1'.
    Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1).PROSITE-ProRule annotation
    NTP + H2O = NDP + phosphate.
    ATP + H2O = ADP + phosphate.

    Cofactori

    Binds 1 zinc ion per NS3 protease domain.By similarity
    Binds 1 zinc ion per NS5A N-terminal domain.By similarity

    Enzyme regulationi

    Activity of auto-protease NS2-3 is dependent on zinc ions and completely inhibited by EDTA. Serine protease NS3 is also activated by zinc ions By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei177 – 1782Cleavage; by host signal peptidaseBy similarity
    Sitei191 – 1922Cleavage; by host signal peptidaseSequence Analysis
    Sitei383 – 3842Cleavage; by host signal peptidaseSequence Analysis
    Sitei747 – 7482Cleavage; by host signal peptidaseBy similarity
    Sitei810 – 8112Cleavage; by host signal peptidaseBy similarity
    Active sitei953 – 9531For protease NS2-3 activity; shared with dimeric partnerPROSITE-ProRule annotation
    Active sitei973 – 9731For protease NS2-3 activity; shared with dimeric partnerPROSITE-ProRule annotation
    Active sitei994 – 9941For protease NS2-3 activity; shared with dimeric partnerPROSITE-ProRule annotation
    Sitei1027 – 10282Cleavage; by protease NS2-3PROSITE-ProRule annotation
    Active sitei1108 – 11081Charge relay system; for serine protease NS3 activityBy similarity
    Metal bindingi1124 – 11241ZincBy similarity
    Metal bindingi1126 – 11261ZincBy similarity
    Active sitei1166 – 11661Charge relay system; for serine protease NS3 activityBy similarity
    Metal bindingi1172 – 11721ZincBy similarity
    Metal bindingi1176 – 11761ZincBy similarity
    Sitei1658 – 16592Cleavage; by serine protease NS3Sequence Analysis
    Sitei1712 – 17132Cleavage; by serine protease NS3Sequence Analysis
    Sitei1973 – 19742Cleavage; by serine protease NS3Sequence Analysis
    Metal bindingi2012 – 20121ZincBy similarity
    Metal bindingi2030 – 20301ZincBy similarity
    Metal bindingi2032 – 20321ZincBy similarity
    Metal bindingi2053 – 20531ZincBy similarity
    Sitei2424 – 24252Cleavage; by serine protease NS3Sequence Analysis

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi1231 – 12388ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. ATP-dependent helicase activity Source: InterPro
    3. cysteine-type endopeptidase activity Source: InterPro
    4. ion channel activity Source: UniProtKB-KW
    5. RNA binding Source: UniProtKB-KW
    6. RNA-directed RNA polymerase activity Source: UniProtKB-KW
    7. serine-type endopeptidase activity Source: InterPro
    8. serine-type exopeptidase activity Source: InterPro
    9. structural molecule activity Source: InterPro
    10. zinc ion binding Source: InterPro

    GO - Biological processi

    1. apoptotic process Source: UniProtKB-KW
    2. clathrin-mediated endocytosis of virus by host cell Source: UniProtKB-KW
    3. fusion of virus membrane with host endosome membrane Source: UniProtKB-KW
    4. induction by virus of host autophagy Source: UniProtKB-KW
    5. modulation by virus of host G1/S transition checkpoint Source: UniProtKB-KW
    6. pore formation by virus in membrane of host cell Source: UniProtKB-KW
    7. protein oligomerization Source: UniProtKB-KW
    8. regulation of transcription, DNA-templated Source: UniProtKB-KW
    9. suppression by virus of host MAVS activity Source: UniProtKB-KW
    10. suppression by virus of host STAT1 activity Source: UniProtKB-KW
    11. suppression by virus of host TRAF activity Source: UniProtKB-KW
    12. suppression by virus of host type I interferon-mediated signaling pathway Source: UniProtKB-KW
    13. transcription, DNA-templated Source: UniProtKB-KW
    14. transformation of host cell by virus Source: InterPro
    15. viral RNA genome replication Source: InterPro
    16. virion attachment to host cell Source: UniProtKB-KW

    Keywords - Molecular functioni

    Helicase, Hydrolase, Ion channel, Nucleotidyltransferase, Protease, Ribonucleoprotein, RNA-directed RNA polymerase, Serine protease, Thiol protease, Transferase, Viral ion channel

    Keywords - Biological processi

    Activation of host autophagy by virus, Apoptosis, Clathrin-mediated endocytosis of virus by host, Fusion of virus membrane with host endosomal membrane, Fusion of virus membrane with host membrane, G1/S host cell cycle checkpoint dysregulation by virus, Host-virus interaction, Inhibition of host innate immune response by virus, Inhibition of host interferon signaling pathway by virus, Inhibition of host MAVS by virus, Inhibition of host RLR pathway by virus, Inhibition of host STAT1 by virus, Inhibition of host TRAFs by virus, Interferon antiviral system evasion, Ion transport, Modulation of host cell cycle by virus, Transcription, Transcription regulation, Transport, Viral attachment to host cell, Viral immunoevasion, Viral penetration into host cytoplasm, Viral RNA replication, Virus endocytosis by host, Virus entry into host cell

    Keywords - Ligandi

    ATP-binding, Metal-binding, Nucleotide-binding, RNA-binding, Viral nucleoprotein, Zinc

    Protein family/group databases

    MEROPSiS29.001.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Genome polyprotein
    Cleaved into the following 11 chains:
    Alternative name(s):
    Capsid protein C
    p21
    Alternative name(s):
    gp32
    gp35
    Alternative name(s):
    NS1
    gp68
    gp70
    Protease NS2-3 (EC:3.4.22.-)
    Short name:
    p23
    Alternative name(s):
    Hepacivirin
    NS3P
    p70
    Alternative name(s):
    p8
    Alternative name(s):
    p27
    Alternative name(s):
    p56
    Alternative name(s):
    NS5B
    p68
    OrganismiHepatitis C virus genotype 6h (isolate VN004) (HCV)
    Taxonomic identifieri356424 [NCBI]
    Taxonomic lineageiVirusesssRNA positive-strand viruses, no DNA stageFlaviviridaeHepacivirus
    Virus hostiHomo sapiens (Human) [TaxID: 9606]
    ProteomesiUP000008104: Genome

    Subcellular locationi

    Chain Core protein p21 : Host endoplasmic reticulum membrane By similarity; Single-pass membrane protein By similarity. Host mitochondrion membrane By similarity; Single-pass type I membrane protein By similarity. Host lipid droplet By similarity
    Note: The C-terminal transmembrane domain of core protein p21 contains an ER signal leading the nascent polyprotein to the ER membrane. Only a minor proportion of core protein is present in the nucleus and an unknown proportion is secreted.
    Chain Core protein p19 : Virion By similarity. Host cytoplasm By similarity. Host nucleus By similarity. Secreted By similarity
    Chain Envelope glycoprotein E1 : Virion membrane Curated; Single-pass type I membrane protein Curated. Host endoplasmic reticulum membrane By similarity; Single-pass type I membrane protein By similarity
    Note: The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase. After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain. These events explain the final topology of the protein. ER retention of E1 is leaky and, in overexpression conditions, only a small fraction reaches the plasma membrane.
    Chain Envelope glycoprotein E2 : Virion membrane Curated; Single-pass type I membrane protein Curated. Host endoplasmic reticulum membrane By similarity; Single-pass type I membrane protein By similarity
    Note: The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase. After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain. These events explain the final topology of the protein. ER retention of E2 is leaky and, in overexpression conditions, only a small fraction reaches the plasma membrane.
    Chain p7 : Host endoplasmic reticulum membrane By similarity; Multi-pass membrane protein By similarity. Host cell membrane By similarity
    Note: The C-terminus of p7 membrane domain acts as a signal sequence. After cleavage by host signal peptidase, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. Only a fraction localizes to the plasma membrane.
    Chain Serine protease NS3 : Host endoplasmic reticulum membrane By similarity; Peripheral membrane protein By similarity
    Note: NS3 is associated to the ER membrane through its binding to NS4A.
    Chain Non-structural protein 4A : Host endoplasmic reticulum membrane Curated; Single-pass type I membrane protein Curated
    Note: Host membrane insertion occurs after processing by the NS3 protease.
    Chain Non-structural protein 5A : Host endoplasmic reticulum membrane By similarity; Peripheral membrane protein By similarity. Host cytoplasmhost perinuclear region By similarity. Host mitochondrion By similarity
    Note: Host membrane insertion occurs after processing by the NS3 protease.
    Chain RNA-directed RNA polymerase : Host endoplasmic reticulum membrane Curated; Single-pass type I membrane protein Curated
    Note: Host membrane insertion occurs after processing by the NS3 protease.

    GO - Cellular componenti

    1. host cell endoplasmic reticulum membrane Source: UniProtKB-SubCell
    2. host cell lipid particle Source: UniProtKB-SubCell
    3. host cell mitochondrial membrane Source: UniProtKB-SubCell
    4. host cell nucleus Source: UniProtKB-SubCell
    5. host cell perinuclear region of cytoplasm Source: UniProtKB-SubCell
    6. host cell plasma membrane Source: UniProtKB-SubCell
    7. integral component of membrane Source: UniProtKB-KW
    8. integral to membrane of host cell Source: UniProtKB-KW
    9. ribonucleoprotein complex Source: UniProtKB-KW
    10. viral envelope Source: UniProtKB-KW
    11. viral nucleocapsid Source: UniProtKB-KW
    12. virion membrane Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Capsid protein, Host cell membrane, Host cytoplasm, Host endoplasmic reticulum, Host lipid droplet, Host membrane, Host mitochondrion, Host nucleus, Membrane, Secreted, Viral envelope protein, Virion

    Pathology & Biotechi

    Keywords - Diseasei

    Oncogene

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed; by hostBy similarity
    Chaini2 – 191190Core protein p21Sequence AnalysisPRO_0000045736Add
    BLAST
    Chaini2 – 177176Core protein p19By similarityPRO_0000045737Add
    BLAST
    Propeptidei178 – 19114ER anchor for the core protein, removed in mature form by host signal peptidaseBy similarityPRO_0000045738Add
    BLAST
    Chaini192 – 383192Envelope glycoprotein E1Sequence AnalysisPRO_0000045739Add
    BLAST
    Chaini384 – 747364Envelope glycoprotein E2Sequence AnalysisPRO_0000045740Add
    BLAST
    Chaini748 – 81063p7By similarityPRO_0000045741Add
    BLAST
    Chaini811 – 1027217Protease NS2-3PROSITE-ProRule annotationPRO_0000045742Add
    BLAST
    Chaini1028 – 1658631Serine protease NS3Sequence AnalysisPRO_0000045743Add
    BLAST
    Chaini1659 – 171254Non-structural protein 4ASequence AnalysisPRO_0000045744Add
    BLAST
    Chaini1713 – 1973261Non-structural protein 4BSequence AnalysisPRO_0000045745Add
    BLAST
    Chaini1974 – 2424451Non-structural protein 5ASequence AnalysisPRO_0000045746Add
    BLAST
    Chaini2425 – 3015591RNA-directed RNA polymeraseSequence AnalysisPRO_0000045747Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserine; by hostBy similarity
    Modified residuei53 – 531Phosphoserine; by hostBy similarity
    Modified residuei99 – 991Phosphoserine; by hostBy similarity
    Modified residuei116 – 1161Phosphoserine; by host PKABy similarity
    Glycosylationi196 – 1961N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi209 – 2091N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi234 – 2341N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi250 – 2501N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi305 – 3051N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi416 – 4161N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi422 – 4221N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi429 – 4291N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi447 – 4471N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi475 – 4751N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi532 – 5321N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi556 – 5561N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi576 – 5761N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi624 – 6241N-linked (GlcNAc...); by hostSequence Analysis
    Glycosylationi646 – 6461N-linked (GlcNAc...); by hostSequence Analysis
    Lipidationi1973 – 19731S-palmitoyl cysteine; by hostBy similarity
    Disulfide bondi2115 ↔ 2163By similarity
    Modified residuei2195 – 21951Phosphoserine; by host; in p56By similarity
    Modified residuei2198 – 21981Phosphoserine; by host; in p58By similarity
    Modified residuei2202 – 22021Phosphoserine; by host; in p58By similarity
    Modified residuei2205 – 22051Phosphoserine; by host; in p58By similarity

    Post-translational modificationi

    Specific enzymatic cleavages in vivo yield mature proteins. The structural proteins, core, E1, E2 and p7 are produced by proteolytic processing by host signal peptidases. The core protein is synthesized as a 21 kDa precursor which is retained in the ER membrane through the hydrophobic signal peptide. Cleavage by the signal peptidase releases the 19 kDa mature core protein. The other proteins (p7, NS2-3, NS3, NS4A, NS4B, NS5A and NS5B) are cleaved by the viral proteases By similarity.By similarity
    Envelope E1 and E2 glycoproteins are highly N-glycosylated.By similarity
    Core protein is phosphorylated by host PKC and PKA.By similarity
    NS5A is phosphorylated in a basal form termed p56. p58 is a hyperphosphorylated form of p56. p56 and p58 coexist in the cell in roughly equivalent amounts. Hyperphosphorylation is dependent on the presence of NS4A. Human AKT1, RPS6KB1/p70S6K, MAP2K1/MEK1, MAP2K6/MKK6 and CSNK1A1/CKI-alpha kinases may be responsible for NS5A phosphorylation By similarity.By similarity
    NS4B is palmitoylated. This modification may play a role in its polymerization or in protein-protein interactions By similarity.By similarity
    The N-terminus of a fraction of NS4B molecules seems to be relocated post-translationally from the cytoplasm to the ER lumen, with a 5th transmembrane segment. The C-terminus of NS2 may be lumenal with a fourth transmembrane segment By similarity.By similarity
    Core protein is ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation.By similarity

    Keywords - PTMi

    Acetylation, Disulfide bond, Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein, Ubl conjugation

    Interactioni

    Subunit structurei

    Core protein is a homomultimer that binds the C-terminal part of E1 and interacts with numerous cellular proteins. Interaction with human STAT1 SH2 domain seems to result in decreased STAT1 phosphorylation, leading to decreased IFN-stimulated gene transcription. In addition to blocking the formation of phosphorylated STAT1, the core protein also promotes ubiquitin-mediated proteasome-dependent degradation of STAT1. Interacts with, and constitutively activates human STAT3. Associates with human LTBR and TNFRSF1A receptors and possibly induces apoptosis. Binds to human SP110 isoform 3/Sp110b, HNRPK, C1QR1, YWHAE, UBE3A/E6AP, DDX3X, APOA2 and RXRA proteins. Interacts with human CREB3 nuclear transcription protein, triggering cell transformation. May interact with human p53. Also binds human cytokeratins KRT8, KRT18, KRT19 and VIM (vimentin). E1 and E2 glycoproteins form a heterodimer that binds to human LDLR, CLDN1, CD81 and SCARB1 receptors. E2 binds and inhibits human EIF2AK2/PKR. Also binds human CD209/DC-SIGN and CLEC4M/DC-SIGNR. p7 forms a homoheptamer in vitro. NS2 forms a homodimer containing a pair of composite active sites at the dimerization interface. NS2 seems to interact with all other non-structural (NS) proteins. NS4A interacts with NS3 serine protease and stabilizes its folding. NS3-NS4A complex is essential for the activation of the latter and allows membrane anchorage of NS3. NS3 interacts with human TANK-binding kinase TBK1 and MAVS. NS4B and NS5A form homodimers and seem to interact with all other non-structural (NS) proteins. NS5A also interacts with human EIF2AK2/PKR, FKBP8, GRB2, BIN1, PIK3R1, SRCAP, VAPB and with most Src-family kinases. NS5B is a homooligomer and interacts with human VAPB, HNRNPA1 and SEPT6 By similarity.By similarity

    Structurei

    3D structure databases

    ProteinModelPortaliO92532.
    SMRiO92532. Positions 2-45, 903-1027, 1030-1658, 1974-2004, 2009-2171, 2425-2987.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini2 – 168167CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini190 – 358169LumenalSequence AnalysisAdd
    BLAST
    Topological domaini380 – 726347LumenalSequence AnalysisAdd
    BLAST
    Topological domaini748 – 75811LumenalSequence AnalysisAdd
    BLAST
    Topological domaini780 – 7834CytoplasmicSequence Analysis
    Topological domaini805 – 81410LumenalSequence Analysis
    Topological domaini836 – 88247CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini904 – 92926LumenalSequence AnalysisAdd
    BLAST
    Topological domaini951 – 1658708CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini1680 – 1806127CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini1828 – 18292LumenalSequence Analysis
    Topological domaini1851 – 18511CytoplasmicSequence Analysis
    Topological domaini1873 – 188210LumenalSequence Analysis
    Topological domaini1904 – 197370CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini2004 – 2994991CytoplasmicSequence AnalysisAdd
    BLAST

    Intramembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Intramembranei1974 – 200330By similarityAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei169 – 18921HelicalSequence AnalysisAdd
    BLAST
    Transmembranei359 – 37921HelicalSequence AnalysisAdd
    BLAST
    Transmembranei727 – 74721HelicalSequence AnalysisAdd
    BLAST
    Transmembranei759 – 77921HelicalSequence AnalysisAdd
    BLAST
    Transmembranei784 – 80421HelicalSequence AnalysisAdd
    BLAST
    Transmembranei815 – 83521HelicalSequence AnalysisAdd
    BLAST
    Transmembranei883 – 90321HelicalSequence AnalysisAdd
    BLAST
    Transmembranei930 – 95021HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1659 – 167921HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1807 – 182721HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1830 – 185021HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1852 – 187221HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1883 – 190321HelicalSequence AnalysisAdd
    BLAST
    Transmembranei2995 – 301521HelicalBy similarityAdd
    BLAST

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini904 – 1027124Peptidase C18PROSITE-ProRule annotationAdd
    BLAST
    Domaini1218 – 1370153Helicase ATP-bindingPROSITE-ProRule annotationAdd
    BLAST
    Domaini2638 – 2756119RdRp catalyticPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni2 – 5958Interaction with DDX3XBy similarityAdd
    BLAST
    Regioni2 – 2322Interaction with STAT1By similarityAdd
    BLAST
    Regioni122 – 17352Interaction with APOA2By similarityAdd
    BLAST
    Regioni150 – 15910Mitochondrial targeting signalBy similarity
    Regioni164 – 1674Important for lipid droplets localizationBy similarity
    Regioni265 – 29632Fusion peptideSequence AnalysisAdd
    BLAST
    Regioni384 – 41027HVR1By similarityAdd
    BLAST
    Regioni482 – 49413CD81-binding 1Sequence AnalysisAdd
    BLAST
    Regioni522 – 55332CD81-binding 2Sequence AnalysisAdd
    BLAST
    Regioni661 – 67212PKR/eIF2-alpha phosphorylation homology domain (PePHD)By similarityAdd
    BLAST
    Regioni1680 – 169112NS3-binding (by NS4A)Sequence AnalysisAdd
    BLAST
    Regioni2201 – 225151Basal phosphorylationBy similarityAdd
    BLAST
    Regioni2211 – 227666PKR-bindingSequence AnalysisAdd
    BLAST
    Regioni2250 – 230859NS4B-bindingSequence AnalysisAdd
    BLAST
    Regioni2353 – 242472Basal phosphorylationBy similarityAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi5 – 139Nuclear localization signalSequence Analysis
    Motifi38 – 436Nuclear localization signalSequence Analysis
    Motifi58 – 647Nuclear localization signalSequence Analysis
    Motifi66 – 716Nuclear localization signalSequence Analysis
    Motifi1317 – 13204DECH boxBy similarity
    Motifi2324 – 23274SH3-bindingSequence Analysis
    Motifi2329 – 23379Nuclear localization signalSequence Analysis

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi797 – 8048Poly-Leu
    Compositional biasi2278 – 232952Pro-richAdd
    BLAST
    Compositional biasi2996 – 30038Poly-Leu

    Domaini

    The transmembrane regions of envelope E1 and E2 glycoproteins are involved in heterodimer formation, ER localization, and assembly of these proteins. Envelope E2 glycoprotein contain a highly variable region called hypervariable region 1 (HVR1). E2 also contains two segments involved in CD81-binding. HVR1 is implicated in the SCARB1-mediated cell entry. CD81-binding regions may be involved in sensitivity and/or resistance to IFN-alpha therapy By similarity.By similarity
    The N-terminus of NS5A act as membrane anchor. The central s part of NS5A seems to be intrinsically disordered and interacts with NS5B and host PKR By similarity.By similarity
    The SH3-binding domain of NS5A is involved in the interaction with human Bin1, GRB2 and Src-family kinases.By similarity
    The N-terminal one-third of serine protease NS3 contains the protease activity. This region contains a zinc atom that does not belong to the active site, but may play a structural rather than a catalytic role. This region is essential for the activity of protease NS2-3, maybe by contributing to the folding of the latter. The helicase activity is located in the C-terminus of NS3 By similarity.By similarity

    Sequence similaritiesi

    Belongs to the hepacivirus polyprotein family.Curated
    Contains 1 helicase ATP-binding domain.PROSITE-ProRule annotation
    Contains 1 peptidase C18 domain.PROSITE-ProRule annotation
    Contains 1 peptidase S29 domain.Curated
    Contains 1 RdRp catalytic domain.PROSITE-ProRule annotation

    Keywords - Domaini

    SH3-binding, Transmembrane, Transmembrane helix

    Family and domain databases

    Gene3Di3.40.50.300. 2 hits.
    InterProiIPR011492. DEAD_Flavivir.
    IPR002521. HCV_core_C.
    IPR002522. HCV_core_N.
    IPR002519. HCV_env.
    IPR002531. HCV_NS1.
    IPR002518. HCV_NS2.
    IPR000745. HCV_NS4a.
    IPR001490. HCV_NS4b.
    IPR002868. HCV_NS5a.
    IPR013193. HCV_NS5a_1B_dom.
    IPR024350. HCV_NS5a_C.
    IPR014001. Helicase_ATP-bd.
    IPR001650. Helicase_C.
    IPR013192. NS5A_1a.
    IPR027417. P-loop_NTPase.
    IPR004109. Peptidase_S29.
    IPR007094. RNA-dir_pol_PSvirus.
    IPR002166. RNA_pol_HCV.
    IPR009003. Trypsin-like_Pept_dom.
    [Graphical view]
    PfamiPF07652. Flavi_DEAD. 1 hit.
    PF01543. HCV_capsid. 1 hit.
    PF01542. HCV_core. 1 hit.
    PF01539. HCV_env. 1 hit.
    PF01560. HCV_NS1. 1 hit.
    PF01538. HCV_NS2. 1 hit.
    PF01006. HCV_NS4a. 1 hit.
    PF01001. HCV_NS4b. 1 hit.
    PF01506. HCV_NS5a. 1 hit.
    PF08300. HCV_NS5a_1a. 1 hit.
    PF08301. HCV_NS5a_1b. 1 hit.
    PF12941. HCV_NS5a_C. 1 hit.
    PF02907. Peptidase_S29. 1 hit.
    PF00998. RdRP_3. 1 hit.
    [Graphical view]
    ProDomiPD001388. HCV_env. 1 hit.
    [Graphical view] [Entries sharing at least one domain]
    SMARTiSM00487. DEXDc. 1 hit.
    [Graphical view]
    SUPFAMiSSF50494. SSF50494. 1 hit.
    SSF52540. SSF52540. 2 hits.
    PROSITEiPS51693. HCV_NS2_PRO. 1 hit.
    PS51192. HELICASE_ATP_BIND_1. 1 hit.
    PS50507. RDRP_SSRNA_POS. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    O92532-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSTLPKPQRK TKRNTNRRPM DVKFPGGGQI VGGVYLLPRR GPRLGVRATR     50
    KTSERSQPRG RRQPIPKARQ PIGRSWGQPG YPWPLYGNEG CGWAGWLLSP 100
    RGSRPNWGPN DPRRRSRNLG KVIDTLTCGL ADLMGYIPVL GGPLGGVAAA 150
    LAHGVRAIED GVNYATGNLP GCSFSIFLLA LLSCLTTPAS AIQVRNASGI 200
    YHLTNDCSNN SIVFEAETII LHLPGCVPCI KVGNGSRCWL SVSPTLAVPN 250
    SSVPIHGFRR HVDLLVGAAA FCSAMYIGDL CGSVFLVGQL FTFRPKHHQV 300
    TQDCNCSIYA GHITGHRMAW DMMLNWSPTV SYVVSSALRV PQLLLEVITG 350
    AHWGVLGALL YFSMVANWAK VIAVLFLFAG ADATTYTGSA VSSTTGAFVS 400
    LFSPGPTQNL QLVNSNGSWH INRTALNCND SLQTGFIAGL FARYKFNSTG 450
    CPERMSKCRP LHSFEQGWGP ISYVNISGSS EDKPYCWHYA PRPCGIVPAR 500
    NVCGPVYCFT PSPVVVGTTD QRGIPTYTWG ENVSDVFLLH SARPPLGAWF 550
    GCTWMNSSGF VKTCGAPPCR IKPTINETDL VCPTDCFRKH PDASFVKCGS 600
    GPWLTPRCMV DYPYRLWHYP CTVNFTIHKV RVFVGGVEHR FNAACNWTRG 650
    DRCELDDRDR FEMSPLLFST TQLAILPCSF TTMPALSTGL IHLHQNIVDI 700
    QYLYGVSTAV VSWAMKWEYV VLAFLVLADA RVCACLWLMF LVGQAEAALE 750
    NVIVLNAASA ASCQGLLWGL IFICCAWHVR GRAVPVTTYA LLQLWPLLLL 800
    ILALPRRAYA FDSEQAASAG LLVLGLITIF TLTPAYKQLL ISMLWWIQYF 850
    IALTEAQLHQ WVPSLLVRGG RDAVILLACL FHPQLGFEVT KILLALLGPL 900
    YLLQYSLLKT PYFVRAHILL RACMFFRGMA RGRYAQAILL RIGAWTGTYI 950
    YDHLAPLSDW ACDGLRDLAV AVEPVVFSPM EKKVITWGAD TAACGDIIAG 1000
    LPVAARRGNL LFLGPADDVK GKGWRLLAPI TAYAQQTRGI VGTIVTSLTG 1050
    RDKNEVEGEI QVVSTATQSF LATAVNGVLW TVYYGAGSKT LAGPKGPVCQ 1100
    MYTNVDQDLV GWPAPAGARS LTPCSCGSSD LYLVTRNADV IPARRRGDNR 1150
    AALLSPRPIS TLKGSSGGPM LCPSGHVAGI FRAAVCTRGV AKSLDFAPVE 1200
    SMQSSQRSPS FSDNTSPPAV PQTYQVGYLH APTGSGKSTK VPAAYAAQGY 1250
    KVLVLNPSVA ATLGFGSYMS TSHGIDPNIR TGVRTITTGG AITYSTYGKF 1300
    LADGGCSGGA YDVIICDECH STDPTTVSGI GTVLDQAETS GVRLTVLATA 1350
    TPPGSVTVPH PNITESALPT TGEIPFYGKA VPLEYIKGGR HLIFCHPKKK 1400
    CDELAKQLVS LGLNAVAFYR GVDVSVIPTS GDVVVCATDA LMTGYTGDFD 1450
    SVIDCNVTVT QVVDFSLDPT FTIETTTVPQ DAVSRSQRRG RTGRGKHGVY 1500
    RYVSQGERPS GMFDSVILCE AYDTGCAWYE LTPAETTVRL RAYLNTPGLP 1550
    VCQDHLEFWE GVFTGLTHID AHFLSQTKQA EENFAYLVAY QATVCARAKA 1600
    PPPSWDTMWK CLIRLKPMLT GPTPLLYRLG PVQNEVVTTH PITKYIMTCM 1650
    SADLEVITST WVLVGGVVAA LAAYCLSVGC VVICGRISTS GKPVLIPDRE 1700
    VLYQQFDEME ECSRHIPYLA EGHLIAEQFK QKVLGLIQST SKQAEELKPA 1750
    VHAAWPKLEQ FWQKQLWNFV SGIQYLAGLS TLPGNPAIAS LMSFSASLTS 1800
    PLSTHQTLLL NILGGWVASQ LANPTASTAF VVSGLAGAAV GSIGLGRVIV 1850
    DVLAGYGAGV SGALVAFKIM CGETPSAEDM VNLLPALLSP GALVVGVVCA 1900
    AILRRHAGPS EGATQWMNRL IAFASRGNHV SPTHYVPETD TSRQIMTILS 1950
    SLTVTSLLRK LHEWINTDWS TPCSSSWLRD IWDWVCEVLS DFKTWLKAKL 2000
    VPALPGVPFL SCQRGFRGTW RGDGICHTTC PCGSEITGHV KNGTMKISGP 2050
    RWCSNVSHRT FPINATTTGP SVPIPEPNYT RALWRVSAEE YVEVKRVGDS 2100
    HFVVGATTDN LKCPCQVPAP EFFTEVDGVR LHRYAPRCKP LLRDEVSFSV 2150
    GLSSYAVGSQ LPCEPEPDVT VVTSMLIDPS HVTAEAAARR LARGSPPSLA 2200
    SSSASQLSAP SLKATCTMHG AHPDAELIEA NLLWRQEMGG NITRVESENK 2250
    VVILDSFDPL VPEFEEREMS VPAECHRPRR PKFPPALPIW ATPGYNPPVL 2300
    ETWKSPTYEP PVVHGCALPP SGPPPIPPPR RKKVVQLDSS NVSAALAQLA 2350
    AKTFETPSSP TTGYGSDQPD HSTESSEHDR DDGVASEAES YSSMPPLEGE 2400
    PGDPDLSSGS WSTVSEEGDS VVCCSYSYSW TGALVTPCAA EEEKLPINPL 2450
    SNSLIRHHNL VYSTSSRSAA TRQKKVTFDR VQLLDQHYYD TVKEIKLRAS 2500
    HVKAQLLSTE EACDLTPPHS ARSKFGYGAK DVRSHASKAI NHINSVWADL 2550
    LEDTQTPIPT TIMAKNEVFC VDASKGGRKS ARLIVYPDLG VRVCEKRALF 2600
    DVTRKLPTAI MGDAYGFQYS PQQRVDRLLK MWRSKKTPMG FSYDTRCFDS 2650
    TVTERDIRTE QDIYLSCQLD PEARKVIESL TERLYVGGPM YNSKGQLCGQ 2700
    RRCRASGVLP TSMGNTVTCF LKATAACRAA GFTDYDMLVC GDDLVVVTES 2750
    AGVNEDIANL RAFTEAMTRY SATPGDEPSP TYDLELITSC SSNVSVAHDG 2800
    DGRRYYYLTR DPVTPLARAA WETARHTPVN SWLGNIIMYA PTIWVRMVLM 2850
    THFFQILQAQ ETLDRALDFD IYGVTYSITP LDLPVIIQRL HGMAAFSLHG 2900
    YSPDELNRVA SCLRKLGAPP LRAWRHRARA VRAKLIAQGG KAAVCGKYLF 2950
    NWAIKTKLRL TPLRGASALD LSGWFTSGYG GGDVYHSASR ARPRFLLLCL 3000
    LLLSVGVGIF LLPAR 3015
    Length:3,015
    Mass (Da):327,978
    Last modified:January 23, 2007 - v3
    Checksum:i69108DD32B5DA012
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D84265 Genomic RNA. Translation: BAA32667.1.

    Cross-referencesi

    Web resourcesi

    euHCVdb

    The European HCV database

    Virus Pathogen Resource

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D84265 Genomic RNA. Translation: BAA32667.1 .

    3D structure databases

    ProteinModelPortali O92532.
    SMRi O92532. Positions 2-45, 903-1027, 1030-1658, 1974-2004, 2009-2171, 2425-2987.
    ModBasei Search...
    MobiDBi Search...

    Protein family/group databases

    MEROPSi S29.001.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Organism-specific databases

    euHCVdbi D84265.

    Family and domain databases

    Gene3Di 3.40.50.300. 2 hits.
    InterProi IPR011492. DEAD_Flavivir.
    IPR002521. HCV_core_C.
    IPR002522. HCV_core_N.
    IPR002519. HCV_env.
    IPR002531. HCV_NS1.
    IPR002518. HCV_NS2.
    IPR000745. HCV_NS4a.
    IPR001490. HCV_NS4b.
    IPR002868. HCV_NS5a.
    IPR013193. HCV_NS5a_1B_dom.
    IPR024350. HCV_NS5a_C.
    IPR014001. Helicase_ATP-bd.
    IPR001650. Helicase_C.
    IPR013192. NS5A_1a.
    IPR027417. P-loop_NTPase.
    IPR004109. Peptidase_S29.
    IPR007094. RNA-dir_pol_PSvirus.
    IPR002166. RNA_pol_HCV.
    IPR009003. Trypsin-like_Pept_dom.
    [Graphical view ]
    Pfami PF07652. Flavi_DEAD. 1 hit.
    PF01543. HCV_capsid. 1 hit.
    PF01542. HCV_core. 1 hit.
    PF01539. HCV_env. 1 hit.
    PF01560. HCV_NS1. 1 hit.
    PF01538. HCV_NS2. 1 hit.
    PF01006. HCV_NS4a. 1 hit.
    PF01001. HCV_NS4b. 1 hit.
    PF01506. HCV_NS5a. 1 hit.
    PF08300. HCV_NS5a_1a. 1 hit.
    PF08301. HCV_NS5a_1b. 1 hit.
    PF12941. HCV_NS5a_C. 1 hit.
    PF02907. Peptidase_S29. 1 hit.
    PF00998. RdRP_3. 1 hit.
    [Graphical view ]
    ProDomi PD001388. HCV_env. 1 hit.
    [Graphical view ] [Entries sharing at least one domain ]
    SMARTi SM00487. DEXDc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF50494. SSF50494. 1 hit.
    SSF52540. SSF52540. 2 hits.
    PROSITEi PS51693. HCV_NS2_PRO. 1 hit.
    PS51192. HELICASE_ATP_BIND_1. 1 hit.
    PS50507. RDRP_SSRNA_POS. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "The entire nucleotide sequences of three hepatitis C virus isolates in genetic groups 7-9 and comparison with those in the other eight genetic groups."
      Tokita H., Okamoto H., Iizuka H., Kishimoto J., Tsuda F., Miyakawa Y., Mayumi M.
      J. Gen. Virol. 79:1847-1857(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
    2. "Properties of the hepatitis C virus core protein: a structural protein that modulates cellular processes."
      McLauchlan J.
      J. Viral Hepat. 7:2-14(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    3. Cited for: REVIEW, SUBCELLULAR LOCATION.
    4. "An RNA-binding protein, hnRNP A1, and a scaffold protein, septin 6, facilitate hepatitis C virus replication."
      Kim C.S., Seol S.K., Song O.-K., Park J.H., Jang S.K.
      J. Virol. 81:3852-3865(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH HNRNPA1 AND SEPT6.

    Entry informationi

    Entry nameiPOLG_HCVVP
    AccessioniPrimary (citable) accession number: O92532
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: January 10, 2006
    Last sequence update: January 23, 2007
    Last modified: October 1, 2014
    This is version 114 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programViral Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    Cell culture adaptation of the virus leads to mutations in NS5A, reducing its inhibitory effect on replication.By similarity
    Core protein exerts viral interference on hepatitis B virus when HCV and HBV coinfect the same cell, by suppressing HBV gene expression, RNA encapsidation and budding.By similarity

    Caution

    The core gene probably also codes for alternative reading frame proteins (ARFPs). Many functions depicted for the core protein might belong to the ARFPs.Curated
    Lacks the conserved His residue in position 1084 essential for serine protease NS3 activity. Its enzyme activity is therefore unsure.Curated

    Keywords - Technical termi

    Complete proteome, Multifunctional enzyme

    Documents

    1. Peptidase families
      Classification of peptidase families and list of entries
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3