ID   POLG_HCVBK              Reviewed;        3010 AA.
AC   P26663;
DT   01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   27-MAR-2024, entry version 235.
DE   RecName: Full=Genome polyprotein;
DE   Contains:
DE     RecName: Full=Core protein precursor;
DE     AltName: Full=Capsid protein C;
DE     AltName: Full=p23;
DE   Contains:
DE     RecName: Full=Mature core protein;
DE     AltName: Full=p21;
DE   Contains:
DE     RecName: Full=Envelope glycoprotein E1;
DE     AltName: Full=gp32;
DE     AltName: Full=gp35;
DE   Contains:
DE     RecName: Full=Envelope glycoprotein E2;
DE     AltName: Full=NS1;
DE     AltName: Full=gp68;
DE     AltName: Full=gp70;
DE   Contains:
DE     RecName: Full=Viroporin p7;
DE   Contains:
DE     RecName: Full=Protease NS2;
DE              Short=p23;
DE              EC=3.4.22.- {ECO:0000269|PubMed:11591719, ECO:0000269|PubMed:9261354};
DE   Contains:
DE     RecName: Full=Serine protease/helicase NS3;
DE              EC=3.4.21.98 {ECO:0000250|UniProtKB:P27958};
DE              EC=3.6.1.15 {ECO:0000250|UniProtKB:P27958};
DE              EC=3.6.4.13 {ECO:0000250|UniProtKB:P27958};
DE     AltName: Full=Hepacivirin;
DE     AltName: Full=NS3 helicase {ECO:0000250|UniProtKB:P27958};
DE     AltName: Full=NS3 protease {ECO:0000250|UniProtKB:P27958};
DE     AltName: Full=NS3P;
DE     AltName: Full=Viroporin p70;
DE   Contains:
DE     RecName: Full=Non-structural protein 4A;
DE              Short=NS4A;
DE     AltName: Full=p8;
DE   Contains:
DE     RecName: Full=Non-structural protein 4B;
DE              Short=NS4B;
DE     AltName: Full=p27;
DE   Contains:
DE     RecName: Full=Non-structural protein 5A;
DE              Short=NS5A;
DE     AltName: Full=p56/58;
DE   Contains:
DE     RecName: Full=RNA-directed RNA polymerase;
DE              EC=2.7.7.48 {ECO:0000269|PubMed:20194503, ECO:0000269|PubMed:9343198};
DE     AltName: Full=NS5B;
DE     AltName: Full=p68;
OS   Hepatitis C virus genotype 1b (isolate BK) (HCV).
OC   Viruses; Riboviria; Orthornavirae; Kitrinoviricota; Flasuviricetes;
OC   Amarillovirales; Flaviviridae; Hepacivirus; Hepacivirus hominis.
OX   NCBI_TaxID=11105;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=1847440; DOI=10.1128/jvi.65.3.1105-1113.1991;
RA   Takamizawa A., Mori C., Fuke I., Manabe S., Murakami S., Fujita J.,
RA   Onishi E., Andoh T., Yoshida I., Okayama H.;
RT   "Structure and organization of the hepatitis C virus genome isolated from
RT   human carriers.";
RL   J. Virol. 65:1105-1113(1991).
RN   [2]
RP   PROTEIN SEQUENCE OF 1487-1500.
RX   PubMed=8647104; DOI=10.1111/j.1432-1033.1996.0611p.x;
RA   Borowski P., Heiland M., Oehlmann K., Becker B., Korneteky L.;
RT   "Non-structural protein 3 of hepatitis C virus inhibits phosphorylation
RT   mediated by cAMP-dependent protein kinase.";
RL   Eur. J. Biochem. 237:611-618(1996).
RN   [3]
RP   SUBCELLULAR LOCATION (MATURE CORE PROTEIN), RNA-BINDING ACTIVITY (MATURE
RP   CORE PROTEIN), AND FUNCTION (MATURE CORE PROTEIN).
RX   PubMed=8189501; DOI=10.1128/jvi.68.6.3631-3641.1994;
RA   Santolini E., Migliaccio G., La Monica N.;
RT   "Biosynthesis and biochemical properties of the hepatitis C virus core
RT   protein.";
RL   J. Virol. 68:3631-3641(1994).
RN   [4]
RP   PROTEOLYTIC CLEAVAGE (GENOME POLYPROTEIN), AND GLYCOSYLATION AT ASN-196.
RX   PubMed=8862403; DOI=10.1006/viro.1996.0510;
RA   Huessy P., Langen H., Mous J., Jacobsen H.;
RT   "Hepatitis C virus core protein: carboxy-terminal boundaries of two
RT   processed species suggest cleavage by a signal peptide peptidase.";
RL   Virology 224:93-104(1996).
RN   [5]
RP   FUNCTION (PROTEASE NS2), PROTEOLYTIC CLEAVAGE (GENOME POLYPROTEIN),
RP   CATALYTIC ACTIVITY (PROTEASE NS2), BIOPHYSICOCHEMICAL PROPERTIES (PROTEASE
RP   NS2), DOMAIN (PROTEASE NS2), AND DOMAIN (SERINE PROTEASE/HELICASE NS3).
RX   PubMed=9261354; DOI=10.1128/jvi.71.9.6373-6380.1997;
RA   Pieroni L., Santolini E., Fipaldini C., Pacini L., Migliaccio G.,
RA   La Monica N.;
RT   "In vitro study of the NS2-3 protease of hepatitis C virus.";
RL   J. Virol. 71:6373-6380(1997).
RN   [6]
RP   FUNCTION (RNA-DIRECTED RNA POLYMERASE), CATALYTIC ACTIVITY (RNA-DIRECTED
RP   RNA POLYMERASE), AND MUTAGENESIS OF ASP-2639; ASP-2644; GLY-2702; THR-2705;
RP   THR-2706; ASN-2710; ASP-2737 AND ASP-2738.
RX   PubMed=9343198; DOI=10.1128/jvi.71.11.8416-8428.1997;
RA   Lohmann V., Koerner F., Herian U., Bartenschlager R.;
RT   "Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA
RT   polymerase and identification of amino acid sequence motifs essential for
RT   enzymatic activity.";
RL   J. Virol. 71:8416-8428(1997).
RN   [7]
RP   FUNCTION (NON-STRUCTURAL PROTEIN 5A), INTERACTION WITH HOST EIF2AK2/PKR
RP   (NON-STRUCTURAL PROTEIN 5A), AND DOMAIN (NON-STRUCTURAL PROTEIN 5A).
RX   PubMed=9710605; DOI=10.1128/mcb.18.9.5208;
RA   Gale M.J. Jr., Blakely C.M., Kwieciszewski B., Tan S.-L., Dossett M.,
RA   Tang N.M., Korth M.J., Polyak S.J., Gretch D.R., Katze M.G.;
RT   "Control of PKR protein kinase by hepatitis C virus nonstructural 5A
RT   protein: molecular mechanisms of kinase regulation.";
RL   Mol. Cell. Biol. 18:5208-5218(1998).
RN   [8]
RP   INTERACTION WITH HOST GRB2 (NON-STRUCTURAL PROTEIN 5A), AND MUTAGENESIS OF
RP   PRO-2322; PRO-2323 AND PRO-2326.
RX   PubMed=10318918; DOI=10.1073/pnas.96.10.5533;
RA   Tan S.-L., Nakao H., He Y., Vijaysri S., Neddermann P., Jacobs B.L.,
RA   Mayer B.J., Katze M.G.;
RT   "NS5A, a nonstructural protein of hepatitis C virus, binds growth factor
RT   receptor-bound protein 2 adaptor protein in a Src homology 3 domain/ligand-
RT   dependent manner and perturbs mitogenic signaling.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:5533-5538(1999).
RN   [9]
RP   PHOSPHORYLATION AT SER-2194, AND MUTAGENESIS OF SER-2194.
RX   PubMed=11118372; DOI=10.1006/viro.2000.0662;
RA   Katze M.G., Kwieciszewski B., Goodlett D.R., Blakely C.M., Neddermann P.,
RA   Tan S.-L., Aebersold R.;
RT   "Ser(2194) is a highly conserved major phosphorylation site of the
RT   hepatitis C virus nonstructural protein NS5A.";
RL   Virology 278:501-513(2000).
RN   [10]
RP   COFACTOR (PROTEASE NS2), CATALYTIC ACTIVITY (PROTEASE NS2), PROTEOLYTIC
RP   CLEAVAGE (GENOME POLYPROTEIN), DOMAIN (SERINE PROTEASE/HELICASE NS3), AND
RP   DOMAIN (PROTEASE NS2).
RX   PubMed=11591719; DOI=10.1074/jbc.m108266200;
RA   Thibeault D., Maurice R., Pilote L., Lamarre D., Pause A.;
RT   "In vitro characterization of a purified NS2/3 protease variant of
RT   hepatitis C virus.";
RL   J. Biol. Chem. 276:46678-46684(2001).
RN   [11]
RP   INTERACTION WITH HOST PIK3R1 (NON-STRUCTURAL PROTEIN 5A).
RX   PubMed=12186904; DOI=10.1128/jvi.76.18.9207-9217.2002;
RA   He Y., Nakao H., Tan S.-L., Polyak S.J., Neddermann P., Vijaysri S.,
RA   Jacobs B.L., Katze M.G.;
RT   "Subversion of cell signaling pathways by hepatitis C virus nonstructural
RT   5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-
RT   kinase.";
RL   J. Virol. 76:9207-9217(2002).
RN   [12]
RP   DOMAIN (ENVELOPE GLYCOPROTEIN E2).
RX   PubMed=12660945; DOI=10.1086/368221;
RA   Hofmann W.P., Sarrazin C., Kronenberger B., Schonberger B., Bruch K.,
RA   Zeuzem S.;
RT   "Mutations within the CD81-binding sites and hypervariable region 2 of the
RT   envelope 2 protein: correlation with treatment response in hepatitis C
RT   virus-infected patients.";
RL   J. Infect. Dis. 187:982-987(2003).
RN   [13]
RP   PHOSPHORYLATION (NON-STRUCTURAL PROTEIN 5A).
RX   PubMed=15016873; DOI=10.1128/jvi.78.7.3502-3513.2004;
RA   Coito C., Diamond D.L., Neddermann P., Korth M.J., Katze M.G.;
RT   "High-throughput screening of the yeast kinome: identification of human
RT   serine/threonine protein kinases that phosphorylate the hepatitis C virus
RT   NS5A protein.";
RL   J. Virol. 78:3502-3513(2004).
RN   [14]
RP   PHOSPHORYLATION BY HOST CSNK1A1 (NON-STRUCTURAL PROTEIN 5A).
RC   STRAIN=Isolate HCV-AT;
RX   PubMed=16943283; DOI=10.1128/jvi.01465-06;
RA   Quintavalle M., Sambucini S., Di Pietro C., De Francesco R., Neddermann P.;
RT   "The alpha isoform of protein kinase CKI is responsible for hepatitis C
RT   virus NS5A hyperphosphorylation.";
RL   J. Virol. 80:11305-11312(2006).
RN   [15]
RP   SUBCELLULAR LOCATION (MATURE CORE PROTEIN).
RX   PubMed=17188392; DOI=10.1016/j.jhep.2006.10.019;
RA   Jackel-Cram C., Babiuk L.A., Liu Q.;
RT   "Up-regulation of fatty acid synthase promoter by hepatitis C virus core
RT   protein: genotype-3a core has a stronger effect than genotype-1b core.";
RL   J. Hepatol. 46:999-1008(2007).
RN   [16]
RP   REVIEW.
RX   PubMed=10718937; DOI=10.1046/j.1365-2893.2000.00201.x;
RA   McLauchlan J.;
RT   "Properties of the hepatitis C virus core protein: a structural protein
RT   that modulates cellular processes.";
RL   J. Viral Hepat. 7:2-14(2000).
RN   [17]
RP   REVIEW.
RX   PubMed=14752815; DOI=10.1002/hep.20032;
RA   Penin F., Dubuisson J., Rey F.A., Moradpour D., Pawlotsky J.-M.;
RT   "Structural biology of hepatitis C virus.";
RL   Hepatology 39:5-19(2004).
RN   [18]
RP   FUNCTION (RNA-DIRECTED RNA POLYMERASE), AND CATALYTIC ACTIVITY
RP   (RNA-DIRECTED RNA POLYMERASE).
RX   PubMed=20194503; DOI=10.1074/jbc.m109.082206;
RA   Reich S., Golbik R.P., Geissler R., Lilie H., Behrens S.E.;
RT   "Mechanisms of activity and inhibition of the hepatitis C virus RNA-
RT   dependent RNA polymerase.";
RL   J. Biol. Chem. 285:13685-13693(2010).
RN   [19] {ECO:0007744|PDB:1A1Q}
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 1027-1215 IN COMPLEX WITH ZINC,
RP   ACTIVE SITE (SERINE PROTEASE/HELICASE NS3), AND COFACTOR (SERINE
RP   PROTEASE/HELICASE NS3).
RX   PubMed=8861916; DOI=10.1016/s0092-8674(00)81350-1;
RA   Love R.A., Parge H.E., Wickersham J.A., Hostomsky Z., Habuka N.,
RA   Moomaw E.W., Adachi T., Hostomska Z.;
RT   "The crystal structure of hepatitis C virus NS3 proteinase reveals a
RT   trypsin-like fold and a structural zinc binding site.";
RL   Cell 87:331-342(1996).
RN   [20] {ECO:0007744|PDB:1JXP, ECO:0007744|PDB:1NS3}
RP   X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1027-1206 AND 1678-1691,
RP   INTERACTION WITH NON-STRUCTURAL PROTEIN 4A (SERINE PROTEASE/HELICASE NS3),
RP   INTERACTION WITH SERINE PROTEASE/HELICASE NS3 (NON-STRUCTURAL PROTEIN 4A),
RP   AND ACTIVE SITE (SERINE PROTEASE/HELICASE NS3).
RX   PubMed=9568891; DOI=10.1002/pro.5560070402;
RA   Yan Y., Li Y., Munshi S., Sardana V., Cole J.L., Sardana M.,
RA   Steinkuehler C., Tomei L., de Francesco R., Kuo L.C., Chen Z.;
RT   "Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a
RT   2.2-A resolution structure in a hexagonal crystal form.";
RL   Protein Sci. 7:837-847(1998).
RN   [21] {ECO:0007744|PDB:8OHM}
RP   X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1216-1650, DOMAIN (SERINE
RP   PROTEASE/HELICASE NS3), RNA-BINDING (SERINE PROTEASE/HELICASE NS3), AND
RP   FUNCTION (SERINE PROTEASE/HELICASE NS3).
RX   PubMed=9614113; DOI=10.1074/jbc.273.24.15045;
RA   Cho H.-S., Ha N.-C., Kang L.-W., Chung K.M., Back S.H., Jang S.K.,
RA   Oh B.-H.;
RT   "Crystal structure of RNA helicase from genotype 1b hepatitis C virus. A
RT   feasible mechanism of unwinding duplex RNA.";
RL   J. Biol. Chem. 273:15045-15052(1998).
RN   [22] {ECO:0007744|PDB:1CU1}
RP   X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1013-1657.
RX   PubMed=10574797; DOI=10.1016/s0969-2126(00)80025-8;
RA   Yao N., Reichert P., Taremi S.S., Prosise W.W., Weber P.C.;
RT   "Molecular views of viral polyprotein processing revealed by the crystal
RT   structure of the hepatitis C virus bifunctional protease-helicase.";
RL   Structure 7:1353-1363(1999).
RN   [23] {ECO:0007744|PDB:1BT7}
RP   STRUCTURE BY NMR OF 1027-1206 IN COMPLEX WITH ZINC, INTERACTION WITH
RP   NON-STRUCTURAL PROTEIN 4A (SERINE PROTEASE/HELICASE NS3), AND INTERACTION
RP   WITH SERINE PROTEASE/HELICASE NS3 (NON-STRUCTURAL PROTEIN 4A).
RX   PubMed=10366511; DOI=10.1006/jmbi.1999.2745;
RA   Barbato G., Cicero D.O., Nardi M.C., Steinkuehler C., Cortese R.,
RA   De Francesco R., Bazzo R.;
RT   "The solution structure of the N-terminal proteinase domain of the
RT   hepatitis C virus (HCV) NS3 protein provides new insights into its
RT   activation and catalytic mechanism.";
RL   J. Mol. Biol. 289:371-384(1999).
RN   [24] {ECO:0007744|PDB:1CSJ}
RP   X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 2420-2950.
RX   PubMed=10557268; DOI=10.1073/pnas.96.23.13034;
RA   Bressanelli S., Tomei L., Roussel A., Incitti I., Vitale R.L., Mathieu M.,
RA   De Francesco R., Rey F.A.;
RT   "Crystal structure of the RNA-dependent RNA polymerase of hepatitis C
RT   virus.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:13034-13039(1999).
RN   [25] {ECO:0007744|PDB:1C2P}
RP   X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 2414-2989.
RX   PubMed=10504728; DOI=10.1038/13305;
RA   Lesburg C.A., Cable M.B., Ferrari E., Hong Z., Mannarino A.F., Weber P.C.;
RT   "Crystal structure of the RNA-dependent RNA polymerase from hepatitis C
RT   virus reveals a fully encircled active site.";
RL   Nat. Struct. Biol. 6:937-943(1999).
RN   [26] {ECO:0007744|PDB:1QUV}
RP   X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 2420-2999.
RX   PubMed=10574802; DOI=10.1016/s0969-2126(00)80031-3;
RA   Ago H., Adachi T., Yoshida A., Yamamoto M., Habuka N., Yatsunami K.,
RA   Miyano M.;
RT   "Crystal structure of the RNA-dependent RNA polymerase of hepatitis C
RT   virus.";
RL   Structure 7:1417-1426(1999).
RN   [27] {ECO:0007744|PDB:1GX5, ECO:0007744|PDB:1GX6}
RP   X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 2420-2955 IN COMPLEX WITH GTP AND
RP   MANGANESE, AND COFACTOR.
RX   PubMed=11884572; DOI=10.1128/jvi.76.7.3482-3492.2002;
RA   Bressanelli S., Tomei L., Rey F.A., De Francesco R.;
RT   "Structural analysis of the hepatitis C virus RNA polymerase in complex
RT   with ribonucleotides.";
RL   J. Virol. 76:3482-3492(2002).
CC   -!- FUNCTION: [Mature core protein]: Packages viral RNA to form a viral
CC       nucleocapsid, and promotes virion budding (Probable). Participates in
CC       the viral particle production as a result of its interaction with the
CC       non-structural protein 5A (By similarity). Binds RNA and may function
CC       as a RNA chaperone to induce the RNA structural rearrangements taking
CC       place during virus replication (Probable). Modulates viral translation
CC       initiation by interacting with viral IRES and 40S ribosomal subunit (By
CC       similarity). Affects various cell signaling pathways, host immunity and
CC       lipid metabolism (Probable). Prevents the establishment of cellular
CC       antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta)
CC       and IFN-gamma signaling pathways and by blocking the formation of
CC       phosphorylated STAT1 and promoting ubiquitin-mediated proteasome-
CC       dependent degradation of STAT1 (By similarity). Activates STAT3 leading
CC       to cellular transformation (By similarity). Regulates the activity of
CC       cellular genes, including c-myc and c-fos (By similarity). May repress
CC       the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in
CC       the cytoplasm (By similarity). Represses cell cycle negative regulating
CC       factor CDKN1A, thereby interrupting an important check point of normal
CC       cell cycle regulation (By similarity). Targets transcription factors
CC       involved in the regulation of inflammatory responses and in the immune
CC       response: suppresses NF-kappa-B activation, and activates AP-1 (By
CC       similarity). Binds to dendritic cells (DCs) via C1QR1, resulting in
CC       down-regulation of T-lymphocytes proliferation (By similarity). Alters
CC       lipid metabolism by interacting with hepatocellular proteins involved
CC       in lipid accumulation and storage (By similarity). Induces up-
CC       regulation of FAS promoter activity, and thereby contributes to the
CC       increased triglyceride accumulation in hepatocytes (steatosis) (By
CC       similarity). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:P29846, ECO:0000250|UniProtKB:Q99IB8,
CC       ECO:0000305, ECO:0000305|PubMed:8189501}.
CC   -!- FUNCTION: [Envelope glycoprotein E1]: Forms a heterodimer with envelope
CC       glycoprotein E2, which mediates virus attachment to the host cell,
CC       virion internalization through clathrin-dependent endocytosis and
CC       fusion with host membrane (By similarity). Fusion with the host cell is
CC       most likely mediated by both E1 and E2, through conformational
CC       rearrangements of the heterodimer required for fusion rather than a
CC       classical class II fusion mechanism (By similarity). E1/E2 heterodimer
CC       binds host apolipoproteins such as APOB and APOE thereby forming a
CC       lipo-viro-particle (LVP) (By similarity). APOE associated to the LVP
CC       allows the initial virus attachment to cell surface receptors such as
CC       the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan-
CC       1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger
CC       receptor class B type I (SCARB1) (By similarity). The cholesterol
CC       transfer activity of SCARB1 allows E2 exposure and binding of E2 to
CC       SCARB1 and the tetraspanin CD81 (By similarity). E1/E2 heterodimer
CC       binding on CD81 activates the epithelial growth factor receptor (EGFR)
CC       signaling pathway (By similarity). Diffusion of the complex E1-E2-EGFR-
CC       SCARB1-CD81 to the cell lateral membrane allows further interaction
CC       with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry
CC       (By similarity). {ECO:0000250|UniProtKB:P27958}.
CC   -!- FUNCTION: [Envelope glycoprotein E2]: Forms a heterodimer with envelope
CC       glycoprotein E1, which mediates virus attachment to the host cell,
CC       virion internalization through clathrin-dependent endocytosis and
CC       fusion with host membrane (By similarity). Fusion with the host cell is
CC       most likely mediated by both E1 and E2, through conformational
CC       rearrangements of the heterodimer required for fusion rather than a
CC       classical class II fusion mechanism (By similarity). The interaction
CC       between envelope glycoprotein E2 and host apolipoprotein E/APOE allows
CC       the proper assembly, maturation and infectivity of the viral particles
CC       (By similarity). This interaction is probably promoted via the up-
CC       regulation of cellular autophagy by the virus (By similarity). E1/E2
CC       heterodimer binds host apolipoproteins such as APOB and APOE thereby
CC       forming a lipo-viro-particle (LVP) (By similarity). APOE associated to
CC       the LVP allows the initial virus attachment to cell surface receptors
CC       such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1),
CC       syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and
CC       scavenger receptor class B type I (SCARB1) (By similarity). The
CC       cholesterol transfer activity of SCARB1 allows E2 exposure and binding
CC       of E2 to SCARB1 and the tetraspanin CD81 (By similarity). E1/E2
CC       heterodimer binding on CD81 activates the epithelial growth factor
CC       receptor (EGFR) signaling pathway (By similarity). Diffusion of the
CC       complex E1-E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows
CC       further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to
CC       finally trigger HCV entry (By similarity). Inhibits host EIF2AK2/PKR
CC       activation, preventing the establishment of an antiviral state (By
CC       similarity). Viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which
CC       are respectively found on dendritic cells (DCs), and on liver
CC       sinusoidal endothelial cells and macrophage-like cells of lymph node
CC       sinuses (By similarity). These interactions allow the capture of
CC       circulating HCV particles by these cells and subsequent facilitated
CC       transmission to permissive cells such as hepatocytes and lymphocyte
CC       subpopulations (By similarity). The interaction between E2 and host
CC       amino acid transporter complex formed by SLC3A2 and SLC7A5/LAT1 may
CC       facilitate viral entry into host cell (By similarity).
CC       {ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958}.
CC   -!- FUNCTION: [Viroporin p7]: Ion channel protein that acts as a viroporin
CC       and plays an essential role in the assembly, envelopment and secretion
CC       of viral particles (By similarity). Regulates the host cell secretory
CC       pathway, which induces the intracellular retention of viral
CC       glycoproteins and favors assembly of viral particles (By similarity).
CC       Creates a pore in acidic organelles and releases Ca(2+) and H(+) in the
CC       cytoplasm of infected cells, leading to a productive viral infection
CC       (By similarity). High levels of cytoplasmic Ca(2+) may trigger membrane
CC       trafficking and transport of viral ER-associated proteins to
CC       viroplasms, sites of viral genome replication (Probable). This ionic
CC       imbalance induces the assembly of the inflammasome complex, which
CC       triggers the maturation of pro-IL-1beta into IL-1beta through the
CC       action of caspase-1 (By similarity). Targets also host mitochondria and
CC       induces mitochondrial depolarization (By similarity). In addition of
CC       its role as a viroporin, acts as a lipid raft adhesion factor (By
CC       similarity). {ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8, ECO:0000305}.
CC   -!- FUNCTION: [Protease NS2]: Cysteine protease required for the
CC       proteolytic auto-cleavage between the non-structural proteins NS2 and
CC       NS3 (Probable) (PubMed:11591719). The N-terminus of NS3 is required for
CC       the function of NS2 protease (active region NS2-3) (PubMed:11591719).
CC       Promotes the initiation of viral particle assembly by mediating the
CC       interaction between structural and non-structural proteins (By
CC       similarity). {ECO:0000250|UniProtKB:Q9WMX2,
CC       ECO:0000269|PubMed:11591719, ECO:0000305|PubMed:9261354}.
CC   -!- FUNCTION: [Serine protease/helicase NS3]: Displays three enzymatic
CC       activities: serine protease with a chymotrypsin-like fold, NTPase and
CC       RNA helicase (PubMed:9614113). NS3 serine protease, in association with
CC       NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-
CC       NS5A and NS5A-NS5B (By similarity). The NS3/NS4A complex prevents
CC       phosphorylation of host IRF3, thus preventing the establishment of
CC       dsRNA induced antiviral state (By similarity). The NS3/NS4A complex
CC       induces host amino acid transporter component SLC3A2, thus contributing
CC       to HCV propagation (By similarity). NS3 RNA helicase binds to RNA and
CC       unwinds both dsDNA and dsRNA in the 3' to 5' direction, and likely
CC       resolves RNA complicated stable secondary structures in the template
CC       strand (By similarity). Binds a single ATP and catalyzes the unzipping
CC       of a single base pair of dsRNA (By similarity). Inhibits host antiviral
CC       proteins TBK1 and IRF3 thereby preventing the establishment of an
CC       antiviral state (By similarity). Cleaves host MAVS/CARDIF thereby
CC       preventing the establishment of an antiviral state (By similarity).
CC       Cleaves host TICAM1/TRIF, thereby disrupting TLR3 signaling and
CC       preventing the establishment of an antiviral state (By similarity).
CC       {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q9WMX2,
CC       ECO:0000269|PubMed:9614113}.
CC   -!- FUNCTION: [Non-structural protein 4A]: Peptide cofactor which forms a
CC       non-covalent complex with the N-terminal of NS3 serine protease (By
CC       similarity). The NS3/NS4A complex prevents phosphorylation of host
CC       IRF3, thus preventing the establishment of dsRNA induced antiviral
CC       state (By similarity). The NS3/NS4A complex induces host amino acid
CC       transporter component SLC3A2, thus contributing to HCV propagation (By
CC       similarity). {ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q9WMX2}.
CC   -!- FUNCTION: [Non-structural protein 4B]: Induces a specific membrane
CC       alteration that serves as a scaffold for the virus replication complex
CC       (By similarity). This membrane alteration gives rise to the so-called
CC       ER-derived membranous web that contains the replication complex (By
CC       similarity). NS4B self-interaction contributes to its function in
CC       membranous web formation (By similarity). Promotes host TRIF protein
CC       degradation in a CASP8-dependent manner thereby inhibiting host TLR3-
CC       mediated interferon signaling (By similarity). Disrupts the interaction
CC       between STING and TBK1 contributing to the inhibition of interferon
CC       signaling (By similarity). {ECO:0000250|UniProtKB:P27958}.
CC   -!- FUNCTION: [Non-structural protein 5A]: Phosphorylated protein that is
CC       indispensable for viral replication and assembly (By similarity). Both
CC       hypo- and hyperphosphorylated states are required for the viral life
CC       cycle (By similarity). The hyperphosphorylated form of NS5A is an
CC       inhibitor of viral replication (By similarity). Involved in RNA-binding
CC       and especially in binding to the viral genome (By similarity). Zinc is
CC       essential for RNA-binding (By similarity). Participates in the viral
CC       particle production as a result of its interaction with the viral
CC       mature core protein (By similarity). Its interaction with host VAPB may
CC       target the viral replication complex to vesicles. Down-regulates viral
CC       IRES translation initiation (By similarity). Mediates interferon
CC       resistance, presumably by interacting with and inhibiting host
CC       EIF2AK2/PKR (By similarity). Prevents BIN1-induced apoptosis (By
CC       similarity). Acts as a transcriptional activator of some host genes
CC       important for viral replication when localized in the nucleus (By
CC       similarity). Via the interaction with host PACSIN2, modulates lipid
CC       droplet formation in order to promote virion assembly (By similarity).
CC       Modulates TNFRSF21/DR6 signaling pathway for viral propagation (By
CC       similarity). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8, ECO:0000250|UniProtKB:Q9WMX2}.
CC   -!- FUNCTION: [RNA-directed RNA polymerase]: RNA-dependent RNA polymerase
CC       that performs primer-template recognition and RNA synthesis during
CC       viral replication. Initiates RNA transcription/replication at a flavin
CC       adenine dinucleotide (FAD), resulting in a 5'- FAD cap on viral RNAs.
CC       In this way, recognition of viral 5' RNA by host pattern recognition
CC       receptors can be bypassed, thereby evading activation of antiviral
CC       pathways. {ECO:0000250|UniProtKB:P27958}.
CC   -!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]:
CC       Reaction=Hydrolysis of four peptide bonds in the viral precursor
CC         polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr
CC         in P1 and Ser or Ala in P1'.; EC=3.4.21.98;
CC         Evidence={ECO:0000250|UniProtKB:P27958};
CC   -!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]:
CC       Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-
CC         diphosphate + H(+) + phosphate; Xref=Rhea:RHEA:23680,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474,
CC         ChEBI:CHEBI:57930, ChEBI:CHEBI:61557; EC=3.6.1.15;
CC         Evidence={ECO:0000250|UniProtKB:P27958};
CC   -!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]:
CC       Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13;
CC         Evidence={ECO:0000250|UniProtKB:P27958};
CC   -!- CATALYTIC ACTIVITY: [RNA-directed RNA polymerase]:
CC       Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC         RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA-
CC         COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395;
CC         EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539,
CC         ECO:0000269|PubMed:20194503, ECO:0000269|PubMed:9343198};
CC   -!- COFACTOR: [Protease NS2]:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:11591719};
CC       Note=Activity of protease NS2 is dependent on zinc ions and completely
CC       inhibited by EDTA. This is probably due to the fact that NS2 protease
CC       activity needs NS3 N-terminus that binds a zinc atom (active region
CC       NS2-3). {ECO:0000305|PubMed:11591719};
CC   -!- COFACTOR: [Serine protease/helicase NS3]:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:8861916};
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:Q9WMX2};
CC       Note=Binds 1 zinc ion which has a structural role (PubMed:8861916). The
CC       magnesium ion is essential for the helicase activity (By similarity).
CC       {ECO:0000250|UniProtKB:Q9WMX2, ECO:0000269|PubMed:8861916};
CC   -!- COFACTOR: [RNA-directed RNA polymerase]:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000305|PubMed:11884572};
CC       Note=Binds 2 magnesium ion that constitute a dinuclear catalytic metal
CC       center. {ECO:0000305|PubMed:11884572};
CC   -!- ACTIVITY REGULATION: Inhibited by the antiviral drug hexamethylene
CC       amiloride (By similarity). Inhibition by amantadine appears to be
CC       genotype-dependent (By similarity). Also inhibited by long-alkyl-chain
CC       iminosugar derivatives (By similarity). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000250|UniProtKB:P27958}.
CC   -!- ACTIVITY REGULATION: [RNA-directed RNA polymerase]: Activity is up-
CC       regulated by PRK2/PKN2-mediated phosphorylation.
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- ACTIVITY REGULATION: [Protease NS2]: Activity of auto-protease NS2 is
CC       dependent on zinc ions and completely inhibited by EDTA, 1,10-
CC       phenanthroline, iodocetamide and N-ethylmaleimide. According to
CC       PubMed:9261354, completely inhibited by the serine protease inhibitors
CC       TLCK and TPCK (PubMed:9261354). According to PubMed:8189501, almost
CC       completely inhibited by TPCK and slightly inhibited by TLCK. Not
CC       inhibited by antipain, aprotinin, E64, PMSF and pepstatin. Also
CC       inhibited by NS2 and NS4A derived peptides. Serine protease/helicase
CC       NS3 is also activated by zinc ions. {ECO:0000269|PubMed:9261354}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES: [Protease NS2]:
CC       Temperature dependence:
CC         Optimum temperature is 20 degrees Celsius.
CC         {ECO:0000269|PubMed:9261354};
CC   -!- SUBUNIT: [Mature core protein]: Homooligomer (By similarity). Interacts
CC       with E1 (via C-terminus) (By similarity). Interacts with the non-
CC       structural protein 5A (By similarity). Interacts (via N-terminus) with
CC       host STAT1 (via SH2 domain); this interaction results in decreased
CC       STAT1 phosphorylation and ubiquitin-mediated proteasome-dependent STAT1
CC       degradation, leading to decreased IFN-stimulated gene transcription (By
CC       similarity). Interacts with host STAT3; this interaction constitutively
CC       activates STAT3 (By similarity). Associates with host LTBR receptor (By
CC       similarity). Interacts with host TNFRSF1A receptor and possibly induces
CC       apoptosis (By similarity). Interacts with host HNRPK (By similarity).
CC       Interacts with host YWHAE (By similarity). Interacts with host
CC       UBE3A/E6AP (By similarity). Interacts with host DDX3X (By similarity).
CC       Interacts with host APOA2 (By similarity). Interacts with host RXRA
CC       protein (By similarity). Interacts with host SP110 isoform 3/Sp110b;
CC       this interaction sequesters the transcriptional corepressor SP110 away
CC       from the nucleus (By similarity). Interacts with host CREB3 nuclear
CC       transcription protein; this interaction triggers cell transformation
CC       (By similarity). Interacts with host ACY3 (By similarity). Interacts
CC       with host C1QR1 (By similarity). Interacts with host RBM24; this
CC       interaction, which enhances the interaction of the mature core protein
CC       with 5'-UTR, may inhibit viral translation and favor replication (By
CC       similarity). Interacts (via N-terminus) with host EIF2AK2/PKR (via N-
CC       terminus); this interaction induces the autophosphorylation of EIF2AK2
CC       (By similarity). Part of the viral assembly initiation complex composed
CC       of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By
CC       similarity). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:P29846,
CC       ECO:0000250|UniProtKB:Q03463, ECO:0000250|UniProtKB:Q5EG65,
CC       ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- SUBUNIT: [Envelope glycoprotein E1]: Forms a heterodimer with envelope
CC       glycoprotein E2 (By similarity). Interacts with mature core protein (By
CC       similarity). Interacts with protease NS2 (By similarity). The
CC       heterodimer E1/E2 interacts with host CLDN1; this interaction plays a
CC       role in viral entry into host cell (By similarity). Interacts with host
CC       SPSB2 (via C-terminus) (By similarity). Part of the viral assembly
CC       initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the
CC       mature core protein (By similarity). Interacts with host NEURL3; this
CC       interaction prevents E1 binding to glycoprotein E2 (By similarity).
CC       {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- SUBUNIT: [Envelope glycoprotein E2]: Forms a heterodimer with envelope
CC       glycoprotein E1 (By similarity). Interacts with host CD81 and SCARB1
CC       receptors; these interactions play a role in viral entry into host cell
CC       (By similarity). Interacts with host EIF2AK2/PKR; this interaction
CC       inhibits EIF2AK2 and probably allows the virus to evade the innate
CC       immune response (By similarity). Interacts with host CD209/DC-SIGN and
CC       CLEC4M/DC-SIGNR (By similarity). Interact with host SPCS1; this
CC       interaction is essential for viral particle assembly (By similarity).
CC       Interacts with protease NS2 (By similarity). The heterodimer E1/E2
CC       interacts with host CLDN1; this interaction plays a role in viral entry
CC       into host cell (By similarity). Part of the viral assembly initiation
CC       complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core
CC       protein (By similarity). Interacts with host SLC3A2/4F2hc; the
CC       interaction may facilitate viral entry into host cell (By similarity).
CC       Interacts with human PLSCR1 (By similarity).
CC       {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8,
CC       ECO:0000250|UniProtKB:Q9WMX2}.
CC   -!- SUBUNIT: [Viroporin p7]: Homohexamer (By similarity). Homoheptamer (By
CC       similarity). Interacts with protease NS2 (By similarity).
CC       {ECO:0000250|UniProtKB:O92972, ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- SUBUNIT: [Protease NS2]: Homodimer (By similarity). Interacts with host
CC       SPCS1; this interaction is essential for viral particle assembly (By
CC       similarity). Interacts with envelope glycoprotein E1 (By similarity).
CC       Interacts with envelope glycoprotein E2 (By similarity). Interacts with
CC       viroporin p7 (By similarity). Interacts with serine protease/helicase
CC       NS3 (By similarity). Part of the replication complex composed of NS2,
CC       NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in
CC       an ER-derived membranous web (By similarity). Part of the viral
CC       assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A
CC       and the mature core protein (By similarity).
CC       {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- SUBUNIT: [Serine protease/helicase NS3]: Interacts with protease NS2
CC       (By similarity). Interacts with non-structural protein 4A; this
CC       interaction stabilizes the folding of NS3 serine protease
CC       (PubMed:9568891, PubMed:10366511). NS3-NS4A interaction is essential
CC       for NS3 activation and allows membrane anchorage of the latter
CC       (PubMed:9568891). NS3/NS4A complex also prevents phosphorylation of
CC       host IRF3, thus preventing the establishment of dsRNA induced antiviral
CC       state (By similarity). Interacts with host MAVS; this interaction leads
CC       to the cleavage and inhibition of host MAVS (By similarity). Interacts
CC       with host TICAM1; this interaction leads to the cleavage and inhibition
CC       of host TICAM1 (By similarity). Interacts with host TANK-binding
CC       kinase/TBK1; this interaction results in the inhibition of the
CC       association between TBK1 and IRF3, which leads to the inhibition of
CC       IRF3 activation (By similarity). Interacts with host RBM24 (By
CC       similarity). Part of the replication complex composed of NS2, NS3,
CC       NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-
CC       derived membranous web (By similarity). Part of the viral assembly
CC       initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the
CC       mature core protein (By similarity). {ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8, ECO:0000250|UniProtKB:Q9WMX2,
CC       ECO:0000269|PubMed:10366511, ECO:0000269|PubMed:9568891}.
CC   -!- SUBUNIT: [Non-structural protein 4A]: Interacts with NS3 serine
CC       protease; this interaction stabilizes the folding of NS3 serine
CC       protease (PubMed:9568891, PubMed:10366511). NS3-NS4A interaction is
CC       essential for NS3 activation and allows membrane anchorage of the
CC       latter (PubMed:9568891). Interacts with non-structural protein 5A (via
CC       N-terminus) (By similarity). Part of the replication complex composed
CC       of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase
CC       embedded in an ER-derived membranous web (By similarity). Part of the
CC       viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A,
CC       NS5A and the mature core protein (By similarity).
CC       {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8, ECO:0000269|PubMed:10366511,
CC       ECO:0000269|PubMed:9568891}.
CC   -!- SUBUNIT: [Non-structural protein 5A]: Monomer (By similarity).
CC       Homodimer; dimerization is required for RNA-binding (By similarity).
CC       Interacts with the mature core protein (By similarity). Interacts (via
CC       N-terminus) with non-structural protein 4A (By similarity). Interacts
CC       with non-structural protein 4B (By similarity). Interacts with RNA-
CC       directed RNA polymerase (By similarity). Part of the viral assembly
CC       initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the
CC       mature core protein (By similarity). Part of the replication complex
CC       composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA
CC       polymerase embedded in an ER-derived membranous web (By similarity).
CC       Interacts with host GRB2 (PubMed:10318918). Interacts with host BIN1
CC       (By similarity). Interacts with host PIK3R1 (PubMed:12186904).
CC       Interacts with host SRCAP (By similarity). Interacts with host FKBP8
CC       (By similarity). Interacts with host VAPB (By similarity). Interacts
CC       with host EIF2AK2/PKR; this interaction leads to disruption of EIF2AK2
CC       dimerization by NS5A and probably allows the virus to evade the innate
CC       immune response (PubMed:9710605). Interacts (via N-terminus) with host
CC       PACSIN2 (via N-terminus); this interaction attenuates protein kinase C
CC       alpha-mediated phosphorylation of PACSIN2 by disrupting the interaction
CC       between PACSIN2 and PRKCA (By similarity). Interacts (via N-terminus)
CC       with host SRC kinase (via SH2 domain) (By similarity). Interacts with
CC       most Src-family kinases (By similarity). Interacts with host IFI27 and
CC       SKP2; promotes the ubiquitin-mediated proteasomal degradation of NS5A
CC       (By similarity). Interacts with host GPS2 (By similarity). Interacts
CC       with host TNFRSF21; this interaction allows the modulation by the virus
CC       of JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent
CC       manner (By similarity). Interacts (via N-terminus) with host CIDEB (via
CC       N-terminus); this interaction seems to regulate the association of HCV
CC       particles with APOE (By similarity). Interacts with host CHKA/Choline
CC       Kinase-alpha; CHKA bridges host PI4KA and NS5A and potentiates NS5A-
CC       stimulated PI4KA activity, which then facilitates the targeting of the
CC       ternary complex to the ER for viral replication (By similarity).
CC       Interacts with host SPSB2 (via C-terminus); this interaction targets
CC       NS5A for ubiquitination and degradation (By similarity). Interacts with
CC       host RAB18; this interaction may promote the association of NS5A and
CC       other replicase components with lipid droplets (By similarity).
CC       Interacts (via region D2) with host PPIA/CYPA; the interaction
CC       stimulates RNA-binding ability of NS5A and is dependent on the
CC       peptidyl-prolyl cis-trans isomerase activity of PPIA/CYPA. Interacts
CC       with host TRIM14; this interaction induces the degradation of NS5A (By
CC       similarity). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8, ECO:0000269|PubMed:10318918,
CC       ECO:0000269|PubMed:12186904, ECO:0000269|PubMed:9710605}.
CC   -!- SUBUNIT: [RNA-directed RNA polymerase]: Homooligomer. Interacts with
CC       non-structural protein 5A (By similarity). Interacts with host VAPB (By
CC       similarity). Interacts with host PRK2/PKN2 (By similarity). Interacts
CC       with host HNRNPA1 and SEPT6; these interactions facilitate the viral
CC       replication (By similarity). Part of the replication complex composed
CC       of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase
CC       embedded in an ER-derived membranous web (By similarity).
CC       {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P27958}.
CC   -!- INTERACTION:
CC       P26663; P52480: Pkm; Xeno; NbExp=3; IntAct=EBI-6857429, EBI-647785;
CC       P26663; Q62245: Sos1; Xeno; NbExp=2; IntAct=EBI-6857429, EBI-1693;
CC       PRO_0000037536; PRO_0000037537 [P26663]: -; NbExp=6; IntAct=EBI-6838571, EBI-6838576;
CC       PRO_0000037536; P04637: TP53; Xeno; NbExp=9; IntAct=EBI-6838571, EBI-366083;
CC       PRO_0000037540; PRO_0000037540 [P26663]: -; NbExp=2; IntAct=EBI-6874437, EBI-6874437;
CC       PRO_0000037540; PRO_0000037548 [Q9WMX2]; Xeno; NbExp=5; IntAct=EBI-6874437, EBI-6863741;
CC   -!- SUBCELLULAR LOCATION: [Core protein precursor]: Host endoplasmic
CC       reticulum membrane {ECO:0000250|UniProtKB:P26664}; Single-pass membrane
CC       protein {ECO:0000255}. Host mitochondrion membrane
CC       {ECO:0000250|UniProtKB:P26664}; Single-pass type I membrane protein
CC       {ECO:0000255}. Note=The C-terminal transmembrane domain of the core
CC       protein precursor contains an ER signal leading the nascent polyprotein
CC       to the ER membrane.
CC   -!- SUBCELLULAR LOCATION: [Mature core protein]: Virion
CC       {ECO:0000250|UniProtKB:Q99IB8}. Host cytoplasm
CC       {ECO:0000250|UniProtKB:P27958}. Host nucleus
CC       {ECO:0000250|UniProtKB:P26662}. Host lipid droplet
CC       {ECO:0000269|PubMed:17188392}. Note=Only a minor proportion of core
CC       protein is present in the nucleus (By similarity). Probably present on
CC       the surface of lipid droplets (PubMed:17188392).
CC       {ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:17188392}.
CC   -!- SUBCELLULAR LOCATION: [Envelope glycoprotein E1]: Virion membrane
CC       {ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host
CC       endoplasmic reticulum membrane; Single-pass type I membrane protein
CC       {ECO:0000250|UniProtKB:P27958}. Note=The C-terminal transmembrane
CC       domain acts as a signal sequence and forms a hairpin structure before
CC       cleavage by host signal peptidase (By similarity). After cleavage, the
CC       membrane sequence is retained at the C-terminus of the protein, serving
CC       as ER membrane anchor (By similarity). A reorientation of the second
CC       hydrophobic stretch occurs after cleavage producing a single reoriented
CC       transmembrane domain (By similarity). These events explain the final
CC       topology of the protein (By similarity).
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- SUBCELLULAR LOCATION: [Envelope glycoprotein E2]: Virion membrane
CC       {ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host
CC       endoplasmic reticulum membrane; Single-pass type I membrane protein
CC       {ECO:0000250|UniProtKB:P27958}. Host lipid droplet
CC       {ECO:0000250|UniProtKB:Q9WMX2}. Note=The C-terminal transmembrane
CC       domain acts as a signal sequence and forms a hairpin structure before
CC       cleavage by host signal peptidase (By similarity). After cleavage, the
CC       membrane sequence is retained at the C-terminus of the protein, serving
CC       as ER membrane anchor (By similarity). A reorientation of the second
CC       hydrophobic stretch occurs after cleavage producing a single reoriented
CC       transmembrane domain (By similarity). These events explain the final
CC       topology of the protein (By similarity).
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- SUBCELLULAR LOCATION: [Viroporin p7]: Host endoplasmic reticulum
CC       membrane {ECO:0000250|UniProtKB:P27958}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:P27958}. Host mitochondrion
CC       {ECO:0000250|UniProtKB:P27958}. Host cell membrane
CC       {ECO:0000250|UniProtKB:P27958}. Note=The C-terminus of p7 membrane
CC       domain acts as a signal sequence (By similarity). After cleavage by
CC       host signal peptidase, the membrane sequence is retained at the C-
CC       terminus of the protein, serving as ER membrane anchor (By similarity).
CC       ER retention of p7 is leaky and a small fraction reaches the plasma
CC       membrane (By similarity). {ECO:0000250|UniProtKB:P27958}.
CC   -!- SUBCELLULAR LOCATION: [Protease NS2]: Host endoplasmic reticulum
CC       membrane {ECO:0000250|UniProtKB:P27958}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:P27958}. Host lipid droplet
CC       {ECO:0000250|UniProtKB:Q9WMX2}. Note=Probably present on the surface of
CC       lipid droplets. {ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- SUBCELLULAR LOCATION: [Serine protease/helicase NS3]: Host endoplasmic
CC       reticulum membrane {ECO:0000305}; Peripheral membrane protein
CC       {ECO:0000305}. Note=NS3 is associated to the ER membrane through its
CC       binding to NS4A. {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Non-structural protein 4A]: Host endoplasmic
CC       reticulum membrane {ECO:0000305}; Single-pass type I membrane protein
CC       {ECO:0000305}. Note=Host membrane insertion occurs after processing by
CC       the NS3 protease.
CC   -!- SUBCELLULAR LOCATION: [Non-structural protein 4B]: Host endoplasmic
CC       reticulum membrane {ECO:0000250|UniProtKB:P27958}; Multi-pass membrane
CC       protein {ECO:0000250|UniProtKB:P27958}. Note=A reorientation of the N-
CC       terminus into the ER lumen occurs post-translationally.
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- SUBCELLULAR LOCATION: [Non-structural protein 5A]: Host endoplasmic
CC       reticulum membrane {ECO:0000250|UniProtKB:P27958}; Peripheral membrane
CC       protein {ECO:0000250|UniProtKB:P27958}. Host cytoplasm, host
CC       perinuclear region {ECO:0000250|UniProtKB:P27958}. Host mitochondrion
CC       {ECO:0000250|UniProtKB:P26662}. Host cytoplasm
CC       {ECO:0000250|UniProtKB:P27958}. Host nucleus
CC       {ECO:0000250|UniProtKB:P26662}. Host lipid droplet
CC       {ECO:0000250|UniProtKB:Q9WMX2}. Note=Host membrane insertion occurs
CC       after processing by the NS3 protease (By similarity). Localizes at the
CC       surface of lipid droplets (By similarity).
CC       {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P27958}.
CC   -!- SUBCELLULAR LOCATION: [RNA-directed RNA polymerase]: Host cytoplasm
CC       {ECO:0000250|UniProtKB:P27958}. Host endoplasmic reticulum membrane;
CC       Single-pass type IV membrane protein {ECO:0000250|UniProtKB:P27958}.
CC       Note=Host membrane insertion occurs after processing by the NS3
CC       protease. {ECO:0000250|UniProtKB:P27958}.
CC   -!- DOMAIN: [Envelope glycoprotein E1]: The transmembrane regions of
CC       envelope E1 and E2 glycoproteins are involved in heterodimer formation,
CC       ER localization, and assembly of these proteins.
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- DOMAIN: [Envelope glycoprotein E2]: The transmembrane regions of
CC       envelope E1 and E2 glycoproteins are involved in heterodimer formation,
CC       ER localization, and assembly of these proteins (By similarity).
CC       Envelope E2 glycoprotein contain two highly variable regions called
CC       hypervariable region 1 and 2 (HVR1 and HVR2) (By similarity). E2 also
CC       contain two segments involved in CD81-binding (PubMed:12660945). HVR1
CC       is implicated in the SCARB1-mediated cell entry and probably acts as a
CC       regulator of the association of particles with lipids (By similarity).
CC       {ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:12660945}.
CC   -!- DOMAIN: [Protease NS2]: The N-terminus of NS3 is required for the
CC       catalytic activity of protease NS2 (PubMed:9261354, PubMed:11591719).
CC       The minimal catalytic region includes the C-terminus of NS2 and the N-
CC       terminus NS3 protease domain (active region NS2-3) (PubMed:11591719).
CC       {ECO:0000269|PubMed:11591719, ECO:0000269|PubMed:9261354}.
CC   -!- DOMAIN: [Serine protease/helicase NS3]: The N-terminal one-third of
CC       serine protease/helicase NS3 contains the protease activity
CC       (PubMed:9261354, PubMed:11591719). This region contains a zinc atom
CC       that does not belong to the active site, but may play a structural
CC       rather than a catalytic role (By similarity). This region is essential
CC       for the activity of protease NS2, maybe by contributing to the folding
CC       of the latter (By similarity). The NTPase/helicase activity is located
CC       in the twothirds C-terminus of NS3, this domain contains the NTPase and
CC       RNA-binding regions (PubMed:9614113). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000269|PubMed:11591719, ECO:0000269|PubMed:9261354,
CC       ECO:0000269|PubMed:9614113}.
CC   -!- DOMAIN: [Non-structural protein 4B]: Contains a glycine zipper region
CC       that critically contributes to the biogenesis of functional ER-derived
CC       replication organelles. {ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- DOMAIN: [Non-structural protein 5A]: The N-terminus of NS5A acts as
CC       membrane anchor (By similarity). The central part of NS5A contains a
CC       variable region called interferon sensitivity determining region (ISDR)
CC       and seems to be intrinsically disordered and interacts with NS5B and
CC       host EIF2AK2 (Probable). The C-terminus of NS5A contains a variable
CC       region called variable region 3 (V3) (By similarity). ISDR and V3 may
CC       be involved in sensitivity and/or resistance to IFN-alpha therapy (By
CC       similarity). The C-terminus contains a nuclear localization signal (By
CC       similarity). The SH3-binding domain is involved in the interaction with
CC       host BIN1, GRB2 and Src-family kinases (By similarity).
CC       {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P27958,
CC       ECO:0000305|PubMed:9710605}.
CC   -!- PTM: [Genome polyprotein]: Specific enzymatic cleavages in vivo yield
CC       mature proteins (By similarity). The structural proteins, core, E1, E2
CC       and p7 are produced by proteolytic processing by host signal peptidases
CC       (By similarity). The core protein precursor is synthesized as a 23 kDa,
CC       which is retained in the ER membrane through the hydrophobic signal
CC       peptide (PubMed:8862403). Cleavage by the signal peptidase releases the
CC       21 kDa mature core protein (PubMed:8862403). The cleavage of the core
CC       protein precursor occurs between aminoacids 176 and 188 but the exact
CC       cleavage site is not known (PubMed:8862403). Some degraded forms of the
CC       core protein appear as well during the course of infection
CC       (PubMed:8862403). The other proteins (p7, NS2, NS3, NS4A, NS4B, NS5A
CC       and NS5B) are cleaved by the viral proteases (By similarity).
CC       Autoprocessing between NS2 and NS3 is mediated by the NS2 cysteine
CC       protease catalytic domain and regulated by the NS3 N-terminal domain
CC       (PubMed:11591719). {ECO:0000250|UniProtKB:P27958,
CC       ECO:0000269|PubMed:11591719, ECO:0000269|PubMed:8862403}.
CC   -!- PTM: [Mature core protein]: Phosphorylated by host PKC and PKA.
CC       {ECO:0000250|UniProtKB:Q01403}.
CC   -!- PTM: [Mature core protein]: Ubiquitinated; mediated by UBE3A and
CC       leading to core protein subsequent proteasomal degradation.
CC       {ECO:0000250|UniProtKB:Q03463}.
CC   -!- PTM: [Envelope glycoprotein E1]: Highly N-glycosylated.
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- PTM: [Envelope glycoprotein E2]: Highly N-glycosylated.
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- PTM: [Protease NS2]: Palmitoylation is required for NS2/3
CC       autoprocessing and E2 recruitment to membranes.
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- PTM: [Non-structural protein 4B]: Palmitoylated. This modification may
CC       play a role in its polymerization or in protein-protein interactions.
CC       {ECO:0000250|UniProtKB:P27958}.
CC   -!- PTM: [Non-structural protein 5A]: Phosphorylated on serines in a basal
CC       form termed p56 (PubMed:11118372). p58 is a hyperphosphorylated form of
CC       p56 (By similarity). p56 and p58 coexist in the cell in roughly
CC       equivalent amounts (By similarity). Hyperphosphorylation is dependent
CC       on the presence of NS4A (By similarity). Host CSNK1A1/CKI-alpha or
CC       RPS6KB1 kinases may be responsible for NS5A phosphorylation
CC       (PubMed:15016873, PubMed:16943283). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000269|PubMed:11118372, ECO:0000269|PubMed:15016873,
CC       ECO:0000269|PubMed:16943283}.
CC   -!- PTM: [Non-structural protein 5A]: Tyrosine phosphorylation is essential
CC       for the interaction with host SRC. {ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- PTM: [RNA-directed RNA polymerase]: The N-terminus is phosphorylated by
CC       host PRK2/PKN2. {ECO:0000250|UniProtKB:P26662}.
CC   -!- MISCELLANEOUS: Viral particle assembly takes place at the surface of
CC       ER-derived membranes in close proximity to lipid droplets. NS2
CC       associates with E1/E2 glycoproteins, NS3 and NS5A, which interacts with
CC       the viral RNA and core protein to promote genome encapsidation. The
CC       nucleocapsid buds at the ER membrane where E1/E2 glycoproteins are
CC       anchored and afterward associate with nascent lipid droplet to acquire
CC       APOE and APOC. Secretion of viral particles is probably regulated by
CC       viroporin p7. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Non-structural protein 5A]: Cell culture adaptation of
CC       the virus leads to mutations in NS5A, reducing its inhibitory effect on
CC       replication. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Mature core protein]: Exerts viral interference on
CC       hepatitis B virus when HCV and HBV coinfect the same cell, by
CC       suppressing HBV gene expression, RNA encapsidation and budding.
CC       {ECO:0000250|UniProtKB:P26662}.
CC   -!- SIMILARITY: Belongs to the hepacivirus polyprotein family.
CC       {ECO:0000305}.
CC   -!- CAUTION: The core gene probably also codes for alternative reading
CC       frame proteins (ARFPs). Many functions depicted for the core protein
CC       might belong to the ARFPs. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Virus Pathogen Resource;
CC       URL="https://www.viprbrc.org/brc/home.spg?decorator=flavi_hcv";
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DR   EMBL; M58335; AAA72945.1; -; Genomic_RNA.
DR   PIR; A38465; GNWVTC.
DR   PDB; 1A1Q; X-ray; 2.40 A; A/B/C=1027-1215.
DR   PDB; 1BT7; NMR; -; A=1027-1206.
DR   PDB; 1C2P; X-ray; 1.90 A; A/B=2422-2989.
DR   PDB; 1CSJ; X-ray; 2.80 A; A/B=2420-2950.
DR   PDB; 1CU1; X-ray; 2.50 A; A/B=1029-1657.
DR   PDB; 1GX5; X-ray; 1.70 A; A=2420-2955.
DR   PDB; 1GX6; X-ray; 1.85 A; A=2420-2950.
DR   PDB; 1JXP; X-ray; 2.20 A; A/B=1027-1206, C/D=1678-1691.
DR   PDB; 1NHU; X-ray; 2.00 A; A/B=2420-2989.
DR   PDB; 1NHV; X-ray; 2.90 A; A/B=2420-2989.
DR   PDB; 1NS3; X-ray; 2.80 A; A/B=1029-1206, C/D=1678-1689.
DR   PDB; 1OS5; X-ray; 2.20 A; A=2420-2989.
DR   PDB; 1QUV; X-ray; 2.50 A; A=2420-2989.
DR   PDB; 2AWZ; X-ray; 2.15 A; A/B=2420-2989.
DR   PDB; 2AX0; X-ray; 2.00 A; A/B=2420-2989.
DR   PDB; 2AX1; X-ray; 2.10 A; A/B=2420-2989.
DR   PDB; 2BRK; X-ray; 2.30 A; A=2420-2955.
DR   PDB; 2BRL; X-ray; 2.40 A; A=2420-2955.
DR   PDB; 2DXS; X-ray; 2.20 A; A/B=2420-2963.
DR   PDB; 2GIQ; X-ray; 1.65 A; A/B=2421-2981.
DR   PDB; 2GIR; X-ray; 1.90 A; A/B=2421-2981.
DR   PDB; 2HAI; X-ray; 1.58 A; A=2420-2988.
DR   PDB; 2HWH; X-ray; 2.30 A; A/B=2422-2989.
DR   PDB; 2HWI; X-ray; 2.00 A; A/B=2422-2989.
DR   PDB; 2I1R; X-ray; 2.20 A; A/B=2422-2989.
DR   PDB; 2JC0; X-ray; 2.20 A; A/B=2420-2989.
DR   PDB; 2JC1; X-ray; 2.00 A; A/B=2420-2989.
DR   PDB; 2O5D; X-ray; 2.20 A; A/B=2422-2989.
DR   PDB; 2WCX; X-ray; 2.00 A; A=2420-2955.
DR   PDB; 2WHO; X-ray; 2.00 A; A/B=2420-2955.
DR   PDB; 2WRM; X-ray; 1.95 A; A=2420-2955.
DR   PDB; 2XWY; X-ray; 2.53 A; A=2420-2955.
DR   PDB; 2ZKU; X-ray; 1.95 A; A/B/C/D=2420-2989.
DR   PDB; 3BR9; X-ray; 2.30 A; A/B=2420-2989.
DR   PDB; 3BSA; X-ray; 2.30 A; A/B=2420-2989.
DR   PDB; 3BSC; X-ray; 2.65 A; A/B=2420-2989.
DR   PDB; 3CDE; X-ray; 2.10 A; A/B=2420-2989.
DR   PDB; 3CIZ; X-ray; 1.87 A; A/B=2421-2989.
DR   PDB; 3CJ0; X-ray; 1.90 A; A/B=2421-2989.
DR   PDB; 3CJ2; X-ray; 1.75 A; A/B=2421-2989.
DR   PDB; 3CJ3; X-ray; 1.87 A; A/B=2421-2989.
DR   PDB; 3CJ4; X-ray; 2.07 A; A/B=2421-2989.
DR   PDB; 3CJ5; X-ray; 1.92 A; A/B=2421-2989.
DR   PDB; 3CO9; X-ray; 2.10 A; A/B=2420-2989.
DR   PDB; 3CVK; X-ray; 2.31 A; A/B=2420-2989.
DR   PDB; 3CWJ; X-ray; 2.40 A; A/B=2420-2989.
DR   PDB; 3D28; X-ray; 2.30 A; A/B=2420-2989.
DR   PDB; 3D5M; X-ray; 2.20 A; A/B=2420-2989.
DR   PDB; 3E51; X-ray; 1.90 A; A/B=2420-2989.
DR   PDB; 3FQK; X-ray; 2.20 A; A/B=2421-2989.
DR   PDB; 3FRZ; X-ray; 1.86 A; A=2420-2989.
DR   PDB; 3G86; X-ray; 2.20 A; A/B=2421-2989.
DR   PDB; 3GYN; X-ray; 2.15 A; A/B=2420-2989.
DR   PDB; 3H2L; X-ray; 1.90 A; A/B=2420-2989.
DR   PDB; 3H59; X-ray; 2.10 A; A/B=2421-2989.
DR   PDB; 3H5S; X-ray; 2.00 A; A/B=2421-2989.
DR   PDB; 3H5U; X-ray; 1.95 A; A/B=2421-2989.
DR   PDB; 3H98; X-ray; 1.90 A; A/B=2421-2989.
DR   PDB; 3IGV; X-ray; 2.60 A; A/B=2420-2989.
DR   PDB; 3MF5; X-ray; 2.00 A; A/B=2421-2989.
DR   PDB; 3RVB; X-ray; 2.20 A; A=1186-1657.
DR   PDB; 3UA7; X-ray; 1.50 A; E/F=2321-2331.
DR   PDB; 3UDL; X-ray; 2.17 A; A/B/C/D=2420-2989.
DR   PDB; 3VQS; X-ray; 1.90 A; A/B/C/D=2420-2989.
DR   PDB; 4A92; X-ray; 2.73 A; A/B=1029-1657, A/B=1678-1690.
DR   PDB; 4B6E; X-ray; 2.46 A; A/B=1029-1657.
DR   PDB; 4B6F; X-ray; 2.89 A; A/B=1029-1657.
DR   PDB; 4B71; X-ray; 2.50 A; A/B=1029-1657.
DR   PDB; 4B73; X-ray; 2.50 A; A/B=1029-1657.
DR   PDB; 4B74; X-ray; 2.18 A; A/B=1029-1657.
DR   PDB; 4B75; X-ray; 2.53 A; A/B=1029-1655.
DR   PDB; 4B76; X-ray; 2.14 A; A/B=1029-1657.
DR   PDB; 4DGV; X-ray; 1.80 A; A=412-423.
DR   PDB; 4DGY; X-ray; 1.80 A; A=412-423.
DR   PDB; 4EO6; X-ray; 1.79 A; A/B=2422-2989.
DR   PDB; 4EO8; X-ray; 1.80 A; A/B=2422-2989.
DR   PDB; 4IH5; X-ray; 1.90 A; A/B=2421-2989.
DR   PDB; 4IH6; X-ray; 2.20 A; A/B=2421-2989.
DR   PDB; 4IH7; X-ray; 2.30 A; A/B=2421-2989.
DR   PDB; 4K8B; X-ray; 2.80 A; C/D=1678-1689.
DR   PDB; 4KAI; X-ray; 2.30 A; A/B=2420-2989.
DR   PDB; 4KB7; X-ray; 1.85 A; A/B=2420-2989.
DR   PDB; 4KBI; X-ray; 2.06 A; A/B=2420-2989.
DR   PDB; 4KE5; X-ray; 2.11 A; A/B=2420-2989.
DR   PDB; 4MIA; X-ray; 2.80 A; A/B=2421-2989.
DR   PDB; 4MIB; X-ray; 2.30 A; A/B=2421-2989.
DR   PDB; 4MK7; X-ray; 2.80 A; A/B=2421-2989.
DR   PDB; 4MK8; X-ray; 2.09 A; A/B=2421-2989.
DR   PDB; 4MK9; X-ray; 2.05 A; A/B=2421-2989.
DR   PDB; 4MKA; X-ray; 2.05 A; A/B=2421-2989.
DR   PDB; 4MKB; X-ray; 1.90 A; A/B=2421-2989.
DR   PDB; 4TN2; X-ray; 2.70 A; A=2422-2989.
DR   PDB; 4WXP; X-ray; 2.08 A; A=1206-1656.
DR   PDB; 5FPS; X-ray; 2.68 A; A/B=1029-1657.
DR   PDB; 5FPT; X-ray; 2.72 A; A/B=1029-1657.
DR   PDB; 5FPY; X-ray; 2.52 A; A/B=1029-1657.
DR   PDB; 5KZP; X-ray; 2.26 A; A/B/C/D=412-423.
DR   PDB; 5W2E; X-ray; 2.80 A; A/B=2422-2989.
DR   PDB; 6MVP; X-ray; 2.00 A; A/B=2420-2989.
DR   PDB; 6W4G; X-ray; 1.95 A; A/B=2421-2981.
DR   PDB; 8OHM; X-ray; 2.30 A; A=1216-1650.
DR   PDBsum; 1A1Q; -.
DR   PDBsum; 1BT7; -.
DR   PDBsum; 1C2P; -.
DR   PDBsum; 1CSJ; -.
DR   PDBsum; 1CU1; -.
DR   PDBsum; 1GX5; -.
DR   PDBsum; 1GX6; -.
DR   PDBsum; 1JXP; -.
DR   PDBsum; 1NHU; -.
DR   PDBsum; 1NHV; -.
DR   PDBsum; 1NS3; -.
DR   PDBsum; 1OS5; -.
DR   PDBsum; 1QUV; -.
DR   PDBsum; 2AWZ; -.
DR   PDBsum; 2AX0; -.
DR   PDBsum; 2AX1; -.
DR   PDBsum; 2BRK; -.
DR   PDBsum; 2BRL; -.
DR   PDBsum; 2DXS; -.
DR   PDBsum; 2GIQ; -.
DR   PDBsum; 2GIR; -.
DR   PDBsum; 2HAI; -.
DR   PDBsum; 2HWH; -.
DR   PDBsum; 2HWI; -.
DR   PDBsum; 2I1R; -.
DR   PDBsum; 2JC0; -.
DR   PDBsum; 2JC1; -.
DR   PDBsum; 2O5D; -.
DR   PDBsum; 2WCX; -.
DR   PDBsum; 2WHO; -.
DR   PDBsum; 2WRM; -.
DR   PDBsum; 2XWY; -.
DR   PDBsum; 2ZKU; -.
DR   PDBsum; 3BR9; -.
DR   PDBsum; 3BSA; -.
DR   PDBsum; 3BSC; -.
DR   PDBsum; 3CDE; -.
DR   PDBsum; 3CIZ; -.
DR   PDBsum; 3CJ0; -.
DR   PDBsum; 3CJ2; -.
DR   PDBsum; 3CJ3; -.
DR   PDBsum; 3CJ4; -.
DR   PDBsum; 3CJ5; -.
DR   PDBsum; 3CO9; -.
DR   PDBsum; 3CVK; -.
DR   PDBsum; 3CWJ; -.
DR   PDBsum; 3D28; -.
DR   PDBsum; 3D5M; -.
DR   PDBsum; 3E51; -.
DR   PDBsum; 3FQK; -.
DR   PDBsum; 3FRZ; -.
DR   PDBsum; 3G86; -.
DR   PDBsum; 3GYN; -.
DR   PDBsum; 3H2L; -.
DR   PDBsum; 3H59; -.
DR   PDBsum; 3H5S; -.
DR   PDBsum; 3H5U; -.
DR   PDBsum; 3H98; -.
DR   PDBsum; 3IGV; -.
DR   PDBsum; 3MF5; -.
DR   PDBsum; 3RVB; -.
DR   PDBsum; 3UA7; -.
DR   PDBsum; 3UDL; -.
DR   PDBsum; 3VQS; -.
DR   PDBsum; 4A92; -.
DR   PDBsum; 4B6E; -.
DR   PDBsum; 4B6F; -.
DR   PDBsum; 4B71; -.
DR   PDBsum; 4B73; -.
DR   PDBsum; 4B74; -.
DR   PDBsum; 4B75; -.
DR   PDBsum; 4B76; -.
DR   PDBsum; 4DGV; -.
DR   PDBsum; 4DGY; -.
DR   PDBsum; 4EO6; -.
DR   PDBsum; 4EO8; -.
DR   PDBsum; 4IH5; -.
DR   PDBsum; 4IH6; -.
DR   PDBsum; 4IH7; -.
DR   PDBsum; 4K8B; -.
DR   PDBsum; 4KAI; -.
DR   PDBsum; 4KB7; -.
DR   PDBsum; 4KBI; -.
DR   PDBsum; 4KE5; -.
DR   PDBsum; 4MIA; -.
DR   PDBsum; 4MIB; -.
DR   PDBsum; 4MK7; -.
DR   PDBsum; 4MK8; -.
DR   PDBsum; 4MK9; -.
DR   PDBsum; 4MKA; -.
DR   PDBsum; 4MKB; -.
DR   PDBsum; 4TN2; -.
DR   PDBsum; 4WXP; -.
DR   PDBsum; 5FPS; -.
DR   PDBsum; 5FPT; -.
DR   PDBsum; 5FPY; -.
DR   PDBsum; 5KZP; -.
DR   PDBsum; 5W2E; -.
DR   PDBsum; 6MVP; -.
DR   PDBsum; 6W4G; -.
DR   PDBsum; 8OHM; -.
DR   BMRB; P26663; -.
DR   SASBDB; P26663; -.
DR   SMR; P26663; -.
DR   IntAct; P26663; 6.
DR   MINT; P26663; -.
DR   BindingDB; P26663; -.
DR   ChEMBL; CHEMBL6040; -.
DR   DrugBank; DB08706; (2S)-({(5Z)-5-[(5-Ethyl-2-furyl)methylene]-4-oxo-4,5-dihydro-1,3-thiazol-2-yl}amino)(4-fluorophenyl)acetic acid.
DR   DrugBank; DB03605; (2s)-2-[(2,4-Dichloro-Benzoyl)-(3-Trifluoromethyl-Benzyl)-Amino]-3-Phenyl-Propionic Acid.
DR   DrugBank; DB02331; (2s)-2-[(5-Benzofuran-2-Yl-Thiophen-2-Ylmethyl)-(2,4-Dichloro-Benzoyl)-Amino]-3-Phenyl-Propionic Acid.
DR   DrugBank; DB07199; (2S,4S,5R)-1-(4-TERT-BUTYLBENZOYL)-2-ISOBUTYL-5-(1,3-THIAZOL-2-YL)PYRROLIDINE-2,4-DICARBOXYLIC ACID.
DR   DrugBank; DB07200; (2S,4S,5R)-2-ISOBUTYL-5-(2-THIENYL)-1-[4-(TRIFLUOROMETHYL)BENZOYL]PYRROLIDINE-2,4-DICARBOXYLIC ACID.
DR   DrugBank; DB07414; (5S)-1-benzyl-3-(1,1-dioxido-1,2-benzisothiazol-3-yl)-4-hydroxy-5-(1-methylethyl)-1,5-dihydro-2H-pyrrol-2-one.
DR   DrugBank; DB08710; (5Z)-5-[(5-ethylfuran-2-yl)methylidene]-2-[[(S)-(4-fluorophenyl)-(2H-tetrazol-5-yl)methyl]amino]-1,3-thiazol-4-one.
DR   DrugBank; DB08390; (6S)-6-CYCLOPENTYL-6-[2-(3-FLUORO-4-ISOPROPOXYPHENYL)ETHYL]-4-HYDROXY-5,6-DIHYDRO-2H-PYRAN-2-ONE.
DR   DrugBank; DB08278; 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone.
DR   DrugBank; DB08701; 2-(3-BROMOPHENYL)-6-[(2-HYDROXYETHYL)AMINO]-1H-BENZO[DE]ISOQUINOLINE-1,3(2H)-DIONE.
DR   DrugBank; DB04298; 3-(4-Amino-2-Tert-Butyl-5-Methyl-Phenylsulfanyl)-6-Cyclopentyl-4-Hydroxy-6-[2-(4-Hydroxy-Phenyl)-Ethyl]-5,6-Dihydro-Pyran-2-One.
DR   DrugBank; DB07570; 3-CYCLOHEXYL-1-(2-MORPHOLIN-4-YL-2-OXOETHYL)-2-PHENYL-1H-INDOLE-6-CARBOXYLIC ACID.
DR   DrugBank; DB08279; 3-{ISOPROPYL[(TRANS-4-METHYLCYCLOHEXYL)CARBONYL]AMINO}-5-PHENYLTHIOPHENE-2-CARBOXYLIC ACID.
DR   DrugBank; DB08581; 4-[(4-bromo-2-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]carbonyl}phenyl)amino]-4-oxobutanoic acid.
DR   DrugBank; DB08578; 4-[(5-bromopyridin-2-yl)amino]-4-oxobutanoic acid.
DR   DrugBank; DB08580; 4-bromo-2-{[(2R)-2-(2-chlorobenzyl)pyrrolidin-1-yl]carbonyl}aniline.
DR   DrugBank; DB08579; 4-bromo-2-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]carbonyl}aniline.
DR   DrugBank; DB08481; 4-Methyl-N-[5-(5-methyl-furan-2-ylmethylene)-4-oxo-thiazolidin-2-ylidene]-benzenesulfonamide.
DR   DrugBank; DB06974; 5-hydroxy-4-(7-methoxy-1,1-dioxido-2H-1,2,4-benzothiadiazin-3-yl)-2-(3-methylbutyl)-6-phenylpyridazin-3(2H)-one.
DR   DrugBank; DB07169; 5R-(3,4-DICHLOROPHENYLMETHYL)-3-(2-THIOPHENESULFONYLAMINO)-4-OXO-2-THIONOTHIAZOLIDINE.
DR   DrugBank; DB11586; Asunaprevir.
DR   DrugBank; DB04137; Guanosine-5'-Triphosphate.
DR   DrugBank; DB08582; N-(4-bromo-2-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]carbonyl}phenyl)-4-morpholin-4-yl-4-oxobutanamide.
DR   DrugBank; DB08031; N-[(13-CYCLOHEXYL-6,7-DIHYDROINDOLO[1,2-D][1,4]BENZOXAZEPIN-10-YL)CARBONYL]-2-METHYL-L-ALANINE.
DR   DrugBank; DB07062; N-{3-[4-Hydroxy-1-(3-methylbutyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxido-2H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide.
DR   DrugBank; DB07238; Nesbuvir.
DR   DrugBank; DB04005; Uridine 5'-triphosphate.
DR   DrugCentral; P26663; -.
DR   MEROPS; S29.001; -.
DR   iPTMnet; P26663; -.
DR   ABCD; P26663; 5 sequenced antibodies.
DR   euHCVdb; M58335; -.
DR   BRENDA; 3.4.21.98; 17002.
DR   EvolutionaryTrace; P26663; -.
DR   Proteomes; UP000007413; Segment.
DR   GO; GO:0044167; C:host cell endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0044186; C:host cell lipid droplet; IEA:UniProtKB-SubCell.
DR   GO; GO:0044191; C:host cell mitochondrial membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR   GO; GO:1990904; C:ribonucleoprotein complex; IEA:UniProtKB-KW.
DR   GO; GO:0019031; C:viral envelope; IEA:UniProtKB-KW.
DR   GO; GO:0019013; C:viral nucleocapsid; IEA:UniProtKB-KW.
DR   GO; GO:0055036; C:virion membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0016887; F:ATP hydrolysis activity; IEA:RHEA.
DR   GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro.
DR   GO; GO:0005216; F:monoatomic ion channel activity; IEA:UniProtKB-KW.
DR   GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR   GO; GO:0003724; F:RNA helicase activity; IEA:UniProtKB-EC.
DR   GO; GO:0003968; F:RNA-dependent RNA polymerase activity; IEA:UniProtKB-KW.
DR   GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro.
DR   GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR   GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
DR   GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR   GO; GO:0075512; P:clathrin-dependent endocytosis of virus by host cell; IEA:UniProtKB-KW.
DR   GO; GO:0039563; P:disruption by virus of host JAK-STAT cascade via inhibition of STAT1 activity; IEA:UniProtKB-KW.
DR   GO; GO:0039527; P:disruption by virus of host TRAF-mediated signal transduction; IEA:UniProtKB-KW.
DR   GO; GO:0039654; P:fusion of virus membrane with host endosome membrane; IEA:UniProtKB-KW.
DR   GO; GO:0039520; P:induction by virus of host autophagy; IEA:UniProtKB-KW.
DR   GO; GO:0039645; P:perturbation by virus of host G1/S transition checkpoint; IEA:UniProtKB-KW.
DR   GO; GO:0051259; P:protein complex oligomerization; IEA:UniProtKB-KW.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR   GO; GO:0039545; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity; IEA:UniProtKB-KW.
DR   GO; GO:0019087; P:transformation of host cell by virus; IEA:InterPro.
DR   GO; GO:0039694; P:viral RNA genome replication; IEA:InterPro.
DR   GO; GO:0019062; P:virion attachment to host cell; IEA:UniProtKB-KW.
DR   GO; GO:0039707; P:virus-mediated pore formation in host cell membrane; IEA:UniProtKB-KW.
DR   CDD; cd17931; DEXHc_viral_Ns3; 1.
DR   CDD; cd20903; HCV_p7; 1.
DR   CDD; cd23202; Hepacivirus_RdRp; 1.
DR   CDD; cd18806; SF2_C_viral; 1.
DR   Gene3D; 2.40.10.120; -; 1.
DR   Gene3D; 3.30.70.270; -; 2.
DR   Gene3D; 6.10.250.1610; -; 1.
DR   Gene3D; 6.10.250.1750; -; 1.
DR   Gene3D; 6.10.250.2920; -; 1.
DR   Gene3D; 2.20.25.210; Hepatitis C NS5A, domain 1B; 1.
DR   Gene3D; 3.30.160.890; Hepatitis C virus envelope glycoprotein E1, chain C; 1.
DR   Gene3D; 2.30.30.710; Hepatitis C virus non-structural protein NS2, C-terminal domain; 1.
DR   Gene3D; 1.20.1280.150; Hepatitis C virus non-structural protein NS2, N-terminal domain; 1.
DR   Gene3D; 2.20.25.220; Hepatitis C virus NS5A, 1B domain; 1.
DR   Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2.
DR   Gene3D; 1.10.820.10; RNA Helicase Chain A , domain 3; 1.
DR   Gene3D; 2.40.10.10; Trypsin-like serine proteases; 1.
DR   InterPro; IPR043502; DNA/RNA_pol_sf.
DR   InterPro; IPR011492; Flavi_DEAD.
DR   InterPro; IPR002521; HCV_Core_C.
DR   InterPro; IPR044896; HCV_core_chain_A.
DR   InterPro; IPR002522; HCV_core_N.
DR   InterPro; IPR002519; HCV_Env.
DR   InterPro; IPR002531; HCV_NS1.
DR   InterPro; IPR002518; HCV_NS2.
DR   InterPro; IPR042205; HCV_NS2_C.
DR   InterPro; IPR042209; HCV_NS2_N.
DR   InterPro; IPR000745; HCV_NS4a.
DR   InterPro; IPR001490; HCV_NS4b.
DR   InterPro; IPR002868; HCV_NS5a.
DR   InterPro; IPR013192; HCV_NS5A_1a.
DR   InterPro; IPR013193; HCV_NS5a_1B_dom.
DR   InterPro; IPR038568; HCV_NS5A_1B_sf.
DR   InterPro; IPR024350; HCV_NS5a_C.
DR   InterPro; IPR014001; Helicase_ATP-bd.
DR   InterPro; IPR001650; Helicase_C.
DR   InterPro; IPR004109; HepC_NS3_protease.
DR   InterPro; IPR038170; NS5A_1a_sf.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   InterPro; IPR009003; Peptidase_S1_PA.
DR   InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
DR   InterPro; IPR043128; Rev_trsase/Diguanyl_cyclase.
DR   InterPro; IPR007094; RNA-dir_pol_PSvirus.
DR   InterPro; IPR002166; RNA_pol_HCV.
DR   Pfam; PF07652; Flavi_DEAD; 1.
DR   Pfam; PF01543; HCV_capsid; 1.
DR   Pfam; PF01542; HCV_core; 1.
DR   Pfam; PF01539; HCV_env; 1.
DR   Pfam; PF01560; HCV_NS1; 1.
DR   Pfam; PF01538; HCV_NS2; 1.
DR   Pfam; PF01006; HCV_NS4a; 1.
DR   Pfam; PF01001; HCV_NS4b; 1.
DR   Pfam; PF01506; HCV_NS5a; 1.
DR   Pfam; PF08300; HCV_NS5a_1a; 1.
DR   Pfam; PF08301; HCV_NS5a_1b; 1.
DR   Pfam; PF12941; HCV_NS5a_C; 1.
DR   Pfam; PF02907; Peptidase_S29; 1.
DR   Pfam; PF00998; RdRP_3; 1.
DR   SMART; SM00487; DEXDc; 1.
DR   SUPFAM; SSF56672; DNA/RNA polymerases; 1.
DR   SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 2.
DR   SUPFAM; SSF50494; Trypsin-like serine proteases; 1.
DR   PROSITE; PS51693; HCV_NS2_PRO; 1.
DR   PROSITE; PS51192; HELICASE_ATP_BIND_1; 1.
DR   PROSITE; PS51194; HELICASE_CTER; 1.
DR   PROSITE; PS51822; HV_PV_NS3_PRO; 1.
DR   PROSITE; PS50507; RDRP_SSRNA_POS; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Activation of host autophagy by virus;
KW   Apoptosis; ATP-binding; Capsid protein;
KW   Clathrin-mediated endocytosis of virus by host; Direct protein sequencing;
KW   Disulfide bond; Fusion of virus membrane with host endosomal membrane;
KW   Fusion of virus membrane with host membrane;
KW   G1/S host cell cycle checkpoint dysregulation by virus; Glycoprotein;
KW   Helicase; Host cell membrane; Host cytoplasm; Host endoplasmic reticulum;
KW   Host lipid droplet; Host membrane; Host mitochondrion; Host nucleus;
KW   Host-virus interaction; Hydrolase;
KW   Inhibition of host innate immune response by virus;
KW   Inhibition of host interferon signaling pathway by virus;
KW   Inhibition of host MAVS by virus; Inhibition of host RLR pathway by virus;
KW   Inhibition of host STAT1 by virus; Inhibition of host TRAFs by virus;
KW   Interferon antiviral system evasion; Ion channel; Ion transport;
KW   Isopeptide bond; Lipoprotein; Magnesium; Membrane; Metal-binding;
KW   Modulation of host cell cycle by virus; Multifunctional enzyme;
KW   Nucleotide-binding; Nucleotidyltransferase; Oncogene; Palmitate;
KW   Phosphoprotein; Protease; Ribonucleoprotein; RNA-binding;
KW   RNA-directed RNA polymerase; Serine protease; SH3-binding; Thiol protease;
KW   Transcription; Transcription regulation; Transferase; Transmembrane;
KW   Transmembrane helix; Transport; Ubl conjugation;
KW   Viral attachment to host cell; Viral envelope protein; Viral immunoevasion;
KW   Viral ion channel; Viral nucleoprotein;
KW   Viral penetration into host cytoplasm; Viral RNA replication; Virion;
KW   Virus endocytosis by host; Virus entry into host cell; Zinc.
FT   INIT_MET        1
FT                   /note="Removed; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P26664"
FT   CHAIN           2..3010
FT                   /note="Genome polyprotein"
FT                   /id="PRO_0000450852"
FT   CHAIN           2..191
FT                   /note="Core protein precursor"
FT                   /id="PRO_0000037529"
FT   CHAIN           2..177
FT                   /note="Mature core protein"
FT                   /id="PRO_0000037530"
FT   PROPEP          178..191
FT                   /note="ER anchor for the core protein, removed in mature
FT                   form by host signal peptidase"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT                   /id="PRO_0000037531"
FT   CHAIN           192..383
FT                   /note="Envelope glycoprotein E1"
FT                   /id="PRO_0000037532"
FT   CHAIN           384..746
FT                   /note="Envelope glycoprotein E2"
FT                   /id="PRO_0000037533"
FT   CHAIN           747..809
FT                   /note="Viroporin p7"
FT                   /id="PRO_0000037534"
FT   CHAIN           810..1026
FT                   /note="Protease NS2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT                   /id="PRO_0000037535"
FT   CHAIN           1027..1657
FT                   /note="Serine protease/helicase NS3"
FT                   /id="PRO_0000037536"
FT   CHAIN           1658..1711
FT                   /note="Non-structural protein 4A"
FT                   /id="PRO_0000037537"
FT   CHAIN           1712..1972
FT                   /note="Non-structural protein 4B"
FT                   /id="PRO_0000037538"
FT   CHAIN           1973..2419
FT                   /note="Non-structural protein 5A"
FT                   /id="PRO_0000037539"
FT   CHAIN           2420..3010
FT                   /note="RNA-directed RNA polymerase"
FT                   /id="PRO_0000037540"
FT   TOPO_DOM        190..358
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TRANSMEM        359..379
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TOPO_DOM        380..725
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TRANSMEM        726..746
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TOPO_DOM        747..757
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TRANSMEM        758..778
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TOPO_DOM        779..781
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TRANSMEM        782..803
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TOPO_DOM        804..813
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TRANSMEM        814..834
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TOPO_DOM        835..838
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TRANSMEM        839..859
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TOPO_DOM        860..881
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TRANSMEM        882..902
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TOPO_DOM        903..1657
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TRANSMEM        1658..1678
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        1679..1805
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1806..1826
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        1827..1828
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1829..1849
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        1850
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1851..1871
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        1872..1881
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1882..1902
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        1903..1972
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   INTRAMEM        1973..2003
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TOPO_DOM        2004..2989
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TRANSMEM        2990..3010
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DOMAIN          903..1026
FT                   /note="Peptidase C18"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT   DOMAIN          1027..1208
FT                   /note="Peptidase S29"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT   DOMAIN          1217..1369
FT                   /note="Helicase ATP-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT   DOMAIN          2633..2751
FT                   /note="RdRp catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT   REGION          2..75
FT                   /note="Disordered"
FT                   /evidence="ECO:0000305|PubMed:8189501"
FT   REGION          2..59
FT                   /note="Interaction with DDX3X"
FT                   /evidence="ECO:0000250|UniProtKB:Q5EG65"
FT   REGION          2..58
FT                   /note="Interaction with EIF2AK2/PKR"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   REGION          2..23
FT                   /note="Interaction with STAT1"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   REGION          112..152
FT                   /note="Important for endoplasmic reticulum and
FT                   mitochondrial localization"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   REGION          122..173
FT                   /note="Interaction with APOA2"
FT                   /evidence="ECO:0000250|UniProtKB:P29846"
FT   REGION          164..167
FT                   /note="Important for lipid droplets localization"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          265..296
FT                   /note="Important for fusion"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          385..411
FT                   /note="HVR1"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          474..482
FT                   /note="HVR2"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          480..494
FT                   /note="CD81-binding 1"
FT                   /evidence="ECO:0000269|PubMed:12660945"
FT   REGION          544..552
FT                   /note="CD81-binding 2"
FT                   /evidence="ECO:0000269|PubMed:12660945"
FT   REGION          660..671
FT                   /note="EIF2AK2/eIF2-alpha phosphorylation homology domain
FT                   (PePHD)"
FT   REGION          904..1206
FT                   /note="Protease NS2-3"
FT                   /evidence="ECO:0000269|PubMed:11591719"
FT   REGION          929..949
FT                   /note="Interaction with host SCPS1"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   REGION          1486..1497
FT                   /note="RNA-binding"
FT                   /evidence="ECO:0000269|PubMed:9614113"
FT   REGION          1679..1690
FT                   /note="NS3-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          1833..1861
FT                   /note="Glycine zipper"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   REGION          1978..1998
FT                   /note="Membrane-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          2005..2221
FT                   /note="RNA-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          2120..2332
FT                   /note="Transcriptional activation"
FT                   /evidence="ECO:0000255"
FT   REGION          2120..2208
FT                   /note="FKBP8-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   REGION          2135..2139
FT                   /note="Interaction with non-structural protein 4A"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   REGION          2189..2441
FT                   /note="Interaction with host SKP2"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          2210..2275
FT                   /note="EIF2AK2/PKR-binding"
FT                   /evidence="ECO:0000269|PubMed:9710605"
FT   REGION          2210..2249
FT                   /note="ISDR"
FT                   /evidence="ECO:0000269|PubMed:9710605"
FT   REGION          2249..2306
FT                   /note="NS4B-binding"
FT                   /evidence="ECO:0000255"
FT   REGION          2332..2441
FT                   /note="Interaction with host IFI27"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          2351..2407
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          2354..2377
FT                   /note="V3"
FT   MOTIF           5..13
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   MOTIF           38..43
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   MOTIF           58..64
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   MOTIF           66..71
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   MOTIF           1316..1319
FT                   /note="DECH box"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   MOTIF           2322..2325
FT                   /note="SH3-binding"
FT                   /evidence="ECO:0000255"
FT   MOTIF           2326..2334
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   COMPBIAS        47..69
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2351..2369
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        952
FT                   /note="For protease NS2 activity; shared with dimeric
FT                   partner"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT   ACT_SITE        972
FT                   /note="For protease NS2 activity; shared with dimeric
FT                   partner"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT   ACT_SITE        993
FT                   /note="For protease NS2 activity; shared with dimeric
FT                   partner"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT   ACT_SITE        1083
FT                   /note="Charge relay system; for serine protease NS3
FT                   activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166,
FT                   ECO:0000269|PubMed:8861916"
FT   ACT_SITE        1107
FT                   /note="Charge relay system; for serine protease NS3
FT                   activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166,
FT                   ECO:0000269|PubMed:8861916"
FT   ACT_SITE        1165
FT                   /note="Charge relay system; for serine protease NS3
FT                   activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166,
FT                   ECO:0000269|PubMed:8861916, ECO:0000269|PubMed:9568891"
FT   BINDING         1123
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="structural; for NS3 protease activity and
FT                   NS2/3 auto-cleavage activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166,
FT                   ECO:0000269|PubMed:10366511, ECO:0000269|PubMed:8861916,
FT                   ECO:0000269|PubMed:9568891"
FT   BINDING         1125
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="structural; for NS3 protease activity and
FT                   NS2/3 auto-cleavage activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166,
FT                   ECO:0000269|PubMed:10366511, ECO:0000269|PubMed:8861916,
FT                   ECO:0000269|PubMed:9568891"
FT   BINDING         1171
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="structural; for NS3 protease activity and
FT                   NS2/3 auto-cleavage activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166,
FT                   ECO:0000269|PubMed:10366511, ECO:0000269|PubMed:8861916"
FT   BINDING         1175
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="structural; for NS3 protease activity and
FT                   NS2/3 auto-cleavage activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166,
FT                   ECO:0000269|PubMed:10366511, ECO:0000269|PubMed:8861916"
FT   BINDING         1230..1237
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT   BINDING         1237
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic; for NS3 helicase activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   BINDING         1317
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic; for NS3 helicase activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   BINDING         2011
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="structural"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   BINDING         2029
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="structural"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   BINDING         2031
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="structural"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   BINDING         2052
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="structural"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   BINDING         2639
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /ligand_note="catalytic; for RNA-directed RNA polymerase
FT                   activity"
FT                   /evidence="ECO:0000305|PubMed:10557268,
FT                   ECO:0000305|PubMed:11884572"
FT   BINDING         2737
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /ligand_note="catalytic; for RNA-directed RNA polymerase
FT                   activity"
FT                   /evidence="ECO:0000305|PubMed:10557268,
FT                   ECO:0000305|PubMed:11884572"
FT   BINDING         2738
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /ligand_note="catalytic; for RNA-directed RNA polymerase
FT                   activity"
FT                   /evidence="ECO:0000305|PubMed:10557268,
FT                   ECO:0000305|PubMed:11884572"
FT   SITE            177..178
FT                   /note="Cleavage; by host signal peptide peptidase"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   SITE            191..192
FT                   /note="Cleavage; by host signal peptidase"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   SITE            383..384
FT                   /note="Cleavage; by host signal peptidase"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   SITE            746..747
FT                   /note="Cleavage; by host signal peptidase"
FT                   /evidence="ECO:0000250"
FT   SITE            809..810
FT                   /note="Cleavage; by host signal peptidase"
FT                   /evidence="ECO:0000250"
FT   SITE            1026..1027
FT                   /note="Cleavage; by protease NS2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT   SITE            1657..1658
FT                   /note="Cleavage; by serine protease/helicase NS3"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   SITE            1711..1712
FT                   /note="Cleavage; by serine protease/helicase NS3"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   SITE            1972..1973
FT                   /note="Cleavage; by serine protease/helicase NS3"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   SITE            2419..2420
FT                   /note="Cleavage; by serine protease/helicase NS3"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   MOD_RES         2
FT                   /note="N-acetylserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q913V3"
FT   MOD_RES         53
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q01403"
FT   MOD_RES         99
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q01403"
FT   MOD_RES         116
FT                   /note="Phosphoserine; by host PKA"
FT                   /evidence="ECO:0000250|UniProtKB:Q01403"
FT   MOD_RES         2194
FT                   /note="Phosphoserine; by host; in p56"
FT                   /evidence="ECO:0000269|PubMed:11118372"
FT   MOD_RES         2197
FT                   /note="Phosphoserine; by host; in p58"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   MOD_RES         2201
FT                   /note="Phosphoserine; by host; in p58"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   MOD_RES         2204
FT                   /note="Phosphoserine; by host; in p58"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   MOD_RES         2207
FT                   /note="Phosphoserine; by host; in p58"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   MOD_RES         2210
FT                   /note="Phosphoserine; by host; in p58"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   MOD_RES         2448
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   MOD_RES         2461
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   LIPID           922
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   LIPID           1968
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   LIPID           1972
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        196
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000269|PubMed:8862403"
FT   CARBOHYD        209
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        234
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        250
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        305
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        417
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        423
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        430
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        448
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        532
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        540
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        556
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        576
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        623
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        645
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        429..552
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        452..459
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        486..494
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        503..508
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        564..569
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        581..585
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        597..620
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        607..644
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        652..677
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CROSSLNK        2350
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   MUTAGEN         2194
FT                   /note="S->A: Loss of phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:11118372"
FT   MUTAGEN         2322
FT                   /note="P->A: Complete loss of binding to GRB2."
FT                   /evidence="ECO:0000269|PubMed:10318918"
FT   MUTAGEN         2323
FT                   /note="P->A: Complete loss of binding to GRB2."
FT                   /evidence="ECO:0000269|PubMed:10318918"
FT   MUTAGEN         2326
FT                   /note="P->A: Complete loss of binding to GRB2."
FT                   /evidence="ECO:0000269|PubMed:10318918"
FT   MUTAGEN         2639
FT                   /note="D->C,G,N: Complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2644
FT                   /note="D->G,N: Complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2702
FT                   /note="G->D,L,R: Complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2705
FT                   /note="T->V: Almost complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2706
FT                   /note="T->C: Almost complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2706
FT                   /note="T->K: Complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2710
FT                   /note="N->K: Complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2736
FT                   /note="G->A,C: Almost complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2737
FT                   /note="D->E,H,N: Complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   MUTAGEN         2738
FT                   /note="D->H: Complete loss of RdRp activity."
FT                   /evidence="ECO:0000269|PubMed:9343198"
FT   STRAND          413..416
FT                   /evidence="ECO:0007829|PDB:4DGY"
FT   STRAND          419..422
FT                   /evidence="ECO:0007829|PDB:4DGY"
FT   STRAND          1017..1023
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1031..1035
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   HELIX           1039..1048
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1057..1063
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1068..1074
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1077..1080
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   HELIX           1082..1085
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1090..1092
FT                   /evidence="ECO:0007829|PDB:1JXP"
FT   STRAND          1095..1097
FT                   /evidence="ECO:0007829|PDB:1JXP"
FT   STRAND          1100..1103
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   TURN            1104..1107
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1108..1112
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1128..1133
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1135..1137
FT                   /evidence="ECO:0007829|PDB:1BT7"
FT   STRAND          1139..1144
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1146..1157
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   HELIX           1158..1161
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1168..1170
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   TURN            1172..1174
FT                   /evidence="ECO:0007829|PDB:1JXP"
FT   STRAND          1176..1186
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1189..1197
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   HELIX           1198..1206
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   STRAND          1224..1229
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1232..1235
FT                   /evidence="ECO:0007829|PDB:1CU1"
FT   TURN            1236..1238
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1239..1246
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1251..1256
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1258..1272
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1277..1279
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1290..1295
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1296..1301
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1307..1309
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1311..1315
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   TURN            1316..1319
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1323..1335
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   TURN            1336..1340
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1342..1350
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1362..1366
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1371..1375
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1378..1380
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1382..1384
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1386..1393
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1397..1409
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1414..1417
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1419..1421
FT                   /evidence="ECO:0007829|PDB:8OHM"
FT   HELIX           1423..1425
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1428..1430
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1432..1436
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1438..1441
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   TURN            1442..1444
FT                   /evidence="ECO:0007829|PDB:8OHM"
FT   STRAND          1448..1453
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1456..1463
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1467..1469
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1471..1478
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1481..1488
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1493..1495
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1497..1503
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1509..1511
FT                   /evidence="ECO:0007829|PDB:4B76"
FT   HELIX           1514..1526
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1532..1544
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1555..1563
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1570..1579
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1584..1596
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1606..1611
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   TURN            1612..1614
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   HELIX           1615..1617
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1625..1629
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1635..1637
FT                   /evidence="ECO:0007829|PDB:8OHM"
FT   HELIX           1640..1650
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   TURN            1653..1655
FT                   /evidence="ECO:0007829|PDB:4WXP"
FT   STRAND          1680..1688
FT                   /evidence="ECO:0007829|PDB:1JXP"
FT   STRAND          2421..2425
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2446..2449
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2453..2455
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2456..2458
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2461..2463
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2464..2471
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2481..2494
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2504..2509
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   TURN            2519..2521
FT                   /evidence="ECO:0007829|PDB:2WRM"
FT   HELIX           2524..2528
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2532..2547
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2549..2551
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2555..2559
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2563..2565
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   TURN            2568..2571
FT                   /evidence="ECO:0007829|PDB:1GX5"
FT   STRAND          2578..2581
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2584..2606
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2607..2609
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2611..2613
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2616..2629
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2630..2638
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2643..2646
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2649..2659
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2666..2678
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   TURN            2679..2681
FT                   /evidence="ECO:0007829|PDB:1GX6"
FT   STRAND          2683..2686
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2688..2690
FT                   /evidence="ECO:0007829|PDB:1CSJ"
FT   STRAND          2692..2696
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2701..2703
FT                   /evidence="ECO:0007829|PDB:2HWI"
FT   HELIX           2706..2724
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2728..2735
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2738..2744
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2748..2764
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2769..2771
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2776..2778
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2779..2781
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2787..2793
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2795..2797
FT                   /evidence="ECO:0007829|PDB:3CVK"
FT   STRAND          2799..2804
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2808..2819
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2826..2833
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   TURN            2834..2836
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2838..2842
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2844..2854
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2858..2860
FT                   /evidence="ECO:0007829|PDB:3BSA"
FT   STRAND          2862..2866
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2869..2873
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2875..2877
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2878..2886
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2888..2891
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2898..2911
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2916..2933
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2935..2944
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2946..2948
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2949..2951
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   HELIX           2959..2962
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   TURN            2967..2970
FT                   /evidence="ECO:0007829|PDB:2GIQ"
FT   STRAND          2976..2978
FT                   /evidence="ECO:0007829|PDB:4KE5"
FT   STRAND          2980..2982
FT                   /evidence="ECO:0007829|PDB:4EO6"
SQ   SEQUENCE   3010 AA;  327194 MW;  F8422D5ECCFDFD9C CRC64;
     MSTNPKPQRK TKRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRAPR KTSERSQPRG
     RRQPIPKARR PEGRTWAQPG YPWPLYGNEG LGWAGWLLSP RGSRPSWGPT DPRRRSRNLG
     KVIDTLTCGF ADLMGYIPLV GAPLGGAARA LAHGVRVLED GVNYATGNLP GCSFSIFLLA
     LLSCLTTPAS AYEVHNVSGI YHVTNDCSNA SIVYEAADLI MHTPGCVPCV REGNSSRCWV
     ALTPTLAARN VTIPTTTIRR HVDLLVGAAA FCSAMYVGDL CGSVFLVSQL FTFSPRRHVT
     LQDCNCSIYP GHVSGHRMAW DMMMNWSPTT ALVVSQLLRI PQAVVDMVAG AHWGVLAGLA
     YYSMAGNWAK VLIVMLLFAG VDGDTHVTGG AQAKTTNRLV SMFASGPSQK IQLINTNGSW
     HINRTALNCN DSLQTGFLAA LFYTHSFNSS GCPERMAQCR TIDKFDQGWG PITYAESSRS
     DQRPYCWHYP PPQCTIVPAS EVCGPVYCFT PSPVVVGTTD RFGVPTYRWG ENETDVLLLN
     NTRPPQGNWF GCTWMNSTGF TKTCGGPPCN IGGVGNNTLT CPTDCFRKHP EATYTKCGSG
     PWLTPRCMVD YPYRLWHYPC TVNFTIFKVR MYVGGVEHRL NAACNWTRGE RCDLEDRDRP
     ELSPLLLSTT EWQVLPCSFT TLPALSTGLI HLHQNIVDVQ YLYGIGSAVV SFAIKWEYVL
     LLFLLLADAR VCACLWMMLL IAQAEAALEN LVVLNSASVA GAHGILSFLV FFCAAWYIKG
     RLVPGATYAL YGVWPLLLLL LALPPRAYAM DREMAASCGG AVFVGLVLLT LSPYYKVFLA
     RLIWWLQYFT TRAEADLHVW IPPLNARGGR DAIILLMCAV HPELIFDITK LLIAILGPLM
     VLQAGITRVP YFVRAQGLIH ACMLVRKVAG GHYVQMAFMK LGALTGTYIY NHLTPLRDWP
     RAGLRDLAVA VEPVVFSDME TKIITWGADT AACGDIILGL PVSARRGKEI LLGPADSLEG
     RGLRLLAPIT AYSQQTRGLL GCIITSLTGR DKNQVEGEVQ VVSTATQSFL ATCVNGVCWT
     VYHGAGSKTL AAPKGPITQM YTNVDQDLVG WPKPPGARSL TPCTCGSSDL YLVTRHADVI
     PVRRRGDSRG SLLSPRPVSY LKGSSGGPLL CPFGHAVGIF RAAVCTRGVA KAVDFVPVES
     METTMRSPVF TDNSSPPAVP QSFQVAHLHA PTGSGKSTKV PAAYAAQGYK VLVLNPSVAA
     TLGFGAYMSK AHGIDPNIRT GVRTITTGAP VTYSTYGKFL ADGGCSGGAY DIIICDECHS
     TDSTTILGIG TVLDQAETAG ARLVVLATAT PPGSVTVPHP NIEEVALSNT GEIPFYGKAI
     PIEAIRGGRH LIFCHSKKKC DELAAKLSGL GINAVAYYRG LDVSVIPTIG DVVVVATDAL
     MTGYTGDFDS VIDCNTCVTQ TVDFSLDPTF TIETTTVPQD AVSRSQRRGR TGRGRRGIYR
     FVTPGERPSG MFDSSVLCEC YDAGCAWYEL TPAETSVRLR AYLNTPGLPV CQDHLEFWES
     VFTGLTHIDA HFLSQTKQAG DNFPYLVAYQ ATVCARAQAP PPSWDQMWKC LIRLKPTLHG
     PTPLLYRLGA VQNEVTLTHP ITKYIMACMS ADLEVVTSTW VLVGGVLAAL AAYCLTTGSV
     VIVGRIILSG RPAIVPDREL LYQEFDEMEE CASHLPYIEQ GMQLAEQFKQ KALGLLQTAT
     KQAEAAAPVV ESKWRALETF WAKHMWNFIS GIQYLAGLST LPGNPAIASL MAFTASITSP
     LTTQSTLLFN ILGGWVAAQL APPSAASAFV GAGIAGAAVG SIGLGKVLVD ILAGYGAGVA
     GALVAFKVMS GEMPSTEDLV NLLPAILSPG ALVVGVVCAA ILRRHVGPGE GAVQWMNRLI
     AFASRGNHVS PTHYVPESDA AARVTQILSS LTITQLLKRL HQWINEDCST PCSGSWLRDV
     WDWICTVLTD FKTWLQSKLL PQLPGVPFFS CQRGYKGVWR GDGIMQTTCP CGAQITGHVK
     NGSMRIVGPK TCSNTWHGTF PINAYTTGPC TPSPAPNYSR ALWRVAAEEY VEVTRVGDFH
     YVTGMTTDNV KCPCQVPAPE FFSEVDGVRL HRYAPACRPL LREEVTFQVG LNQYLVGSQL
     PCEPEPDVAV LTSMLTDPSH ITAETAKRRL ARGSPPSLAS SSASQLSAPS LKATCTTHHV
     SPDADLIEAN LLWRQEMGGN ITRVESENKV VVLDSFDPLR AEEDEREVSV PAEILRKSKK
     FPAAMPIWAR PDYNPPLLES WKDPDYVPPV VHGCPLPPIK APPIPPPRRK RTVVLTESSV
     SSALAELATK TFGSSESSAV DSGTATALPD QASDDGDKGS DVESYSSMPP LEGEPGDPDL
     SDGSWSTVSE EASEDVVCCS MSYTWTGALI TPCAAEESKL PINALSNSLL RHHNMVYATT
     SRSAGLRQKK VTFDRLQVLD DHYRDVLKEM KAKASTVKAK LLSVEEACKL TPPHSAKSKF
     GYGAKDVRNL SSKAVNHIHS VWKDLLEDTV TPIDTTIMAK NEVFCVQPEK GGRKPARLIV
     FPDLGVRVCE KMALYDVVST LPQVVMGSSY GFQYSPGQRV EFLVNTWKSK KNPMGFSYDT
     RCFDSTVTEN DIRVEESIYQ CCDLAPEARQ AIKSLTERLY IGGPLTNSKG QNCGYRRCRA
     SGVLTTSCGN TLTCYLKASA ACRAAKLQDC TMLVNGDDLV VICESAGTQE DAASLRVFTE
     AMTRYSAPPG DPPQPEYDLE LITSCSSNVS VAHDASGKRV YYLTRDPTTP LARAAWETAR
     HTPVNSWLGN IIMYAPTLWA RMILMTHFFS ILLAQEQLEK ALDCQIYGAC YSIEPLDLPQ
     IIERLHGLSA FSLHSYSPGE INRVASCLRK LGVPPLRVWR HRARSVRARL LSQGGRAATC
     GKYLFNWAVK TKLKLTPIPA ASRLDLSGWF VAGYSGGDIY HSLSRARPRW FMLCLLLLSV
     GVGIYLLPNR
//