ID   POLG_HCVED              Reviewed;        3008 AA.
AC   O39929;
DT   10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   27-MAR-2024, entry version 172.
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:0000250|UniProtKB:P26663};
DE     AltName: Full=Non-structural protein 2;
DE              Short=NS2;
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:0000250|UniProtKB:P27958};
DE     AltName: Full=NS5B;
DE     AltName: Full=p68;
OS   Hepatitis C virus genotype 4a (isolate ED43) (HCV).
OC   Viruses; Riboviria; Orthornavirae; Kitrinoviricota; Flasuviricetes;
OC   Amarillovirales; Flaviviridae; Hepacivirus; Hepacivirus hominis.
OX   NCBI_TaxID=356418;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=9191927; DOI=10.1099/0022-1317-78-6-1341;
RA   Chamberlain R.W., Adams N., Saeed A.A., Simmonds P., Elliott R.M.;
RT   "Complete nucleotide sequence of a type 4 hepatitis C virus variant, the
RT   predominant genotype in the Middle East.";
RL   J. Gen. Virol. 78:1341-1347(1997).
RN   [2]
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   [3]
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).
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 (By similarity). Modulates viral
CC       translation initiation by interacting with viral IRES and 40S ribosomal
CC       subunit (By similarity). Affects various cell signaling pathways, host
CC       immunity and lipid metabolism (Probable). Prevents the establishment of
CC       cellular antiviral state by blocking the interferon-alpha/beta (IFN-
CC       alpha/beta) and IFN-gamma signaling pathways and by blocking the
CC       formation of phosphorylated STAT1 and promoting ubiquitin-mediated
CC       proteasome-dependent degradation of STAT1 (By similarity). Activates
CC       STAT3 leading to cellular transformation (By similarity). Regulates the
CC       activity of cellular genes, including c-myc and c-fos (By similarity).
CC       May repress the promoter of p53, and sequester CREB3 and SP110 isoform
CC       3/Sp110b in the cytoplasm (By similarity). Represses cell cycle
CC       negative regulating factor CDKN1A, thereby interrupting an important
CC       check point of normal cell cycle regulation (By similarity). Targets
CC       transcription factors involved in the regulation of inflammatory
CC       responses and in the immune response: suppresses TNF-induced NF-kappa-B
CC       activation, and activates AP-1 (By similarity). Binds to dendritic
CC       cells (DCs) via C1QR1, resulting in down-regulation of T-lymphocytes
CC       proliferation (By similarity). Alters lipid metabolism by interacting
CC       with hepatocellular proteins involved in lipid accumulation and storage
CC       (By similarity). Induces up-regulation of FAS promoter activity, and
CC       thereby contributes to the increased triglyceride accumulation in
CC       hepatocytes (steatosis) (By 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}.
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 (By similarity). The N-terminus of NS3 is required for the function
CC       of NS2 protease (active region NS2-3) (By similarity). Promotes the
CC       initiation of viral particle assembly by mediating the interaction
CC       between structural and non-structural proteins (By similarity).
CC       {ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P27958}.
CC   -!- FUNCTION: [Serine protease/helicase NS3]: Displays three enzymatic
CC       activities: serine protease with a chymotrypsin-like fold, NTPase and
CC       RNA helicase (By similarity). 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   -!- 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 mature
CC       viral core protein (By similarity). Its interaction with host VAPB may
CC       target the viral replication complex to vesicles (By similarity). Down-
CC       regulates viral IRES translation initiation (By similarity). Mediates
CC       interferon resistance, presumably by interacting with and inhibiting
CC       host 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   -!- COFACTOR: [Protease NS2]:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000250|UniProtKB:P26663};
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:0000250|UniProtKB:P26663};
CC   -!- COFACTOR: [Serine protease/helicase NS3]:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000250|UniProtKB:P26663};
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 (By similarity). The
CC       magnesium ion is essential for the helicase activity (By similarity).
CC       {ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:Q9WMX2};
CC   -!- COFACTOR: [RNA-directed RNA polymerase]:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:P26663};
CC       Note=Binds 2 magnesium ion that constitute a dinuclear catalytic metal
CC       center. {ECO:0000250|UniProtKB:P26663};
CC   -!- ACTIVITY REGULATION: [Viroporin p7]: Inhibited by the antiviral drug
CC       hexamethylene amiloride (By similarity). Inhibition by amantadine
CC       appears to be genotype-dependent (By similarity). Also inhibited by
CC       long-alkyl-chain iminosugar derivatives (By similarity).
CC       {ECO:0000250|UniProtKB:P26662, 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   -!- 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). Interacts 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 with host EIF2AK2/PKR; this interaction induces
CC       the autophosphorylation of EIF2AK2 (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:P26662, ECO:0000250|UniProtKB:P26664,
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 (By
CC       similarity). NS3-NS4A interaction is essential for NS3 activation and
CC       allows membrane anchorage of the latter (By similarity). NS3/NS4A
CC       complex also prevents phosphorylation of host IRF3, thus preventing the
CC       establishment of dsRNA induced antiviral state (By similarity).
CC       Interacts with host MAVS; this interaction leads to the cleavage and
CC       inhibition of host MAVS (By similarity). Interacts with host TICAM1;
CC       this interaction leads to the cleavage and inhibition of host TICAM1
CC       (By similarity). Interacts with host TANK-binding kinase/TBK1; this
CC       interaction results in the inhibition of the association between TBK1
CC       and IRF3, which leads to the inhibition of IRF3 activation (By
CC       similarity). Interacts with host RBM24 (By similarity). Part of the
CC       replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-
CC       directed RNA polymerase embedded in an ER-derived membranous web (By
CC       similarity). Part of the viral assembly initiation complex composed of
CC       NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By
CC       similarity). {ECO:0000250|UniProtKB:P26663,
CC       ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8,
CC       ECO:0000250|UniProtKB:Q9WMX2}.
CC   -!- SUBUNIT: [Non-structural protein 4A]: Interacts with NS3 serine
CC       protease; this interaction stabilizes the folding of NS3 serine
CC       protease (By similarity). NS3-NS4A interaction is essential for NS3
CC       activation and allows membrane anchorage of the latter (By similarity).
CC       Interacts with non-structural protein 5A (via N-terminus) (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:P26662,
CC       ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- SUBUNIT: [Non-structural protein 4B]: Homomultimer (By similarity).
CC       Interacts with non-structural protein NS5A (By similarity). Interacts
CC       with host PLA2G4C; this interaction likely initiates the recruitment of
CC       replication complexes to lipid droplets (By similarity). Interacts with
CC       host STING; this interaction disrupts the interaction between STING and
CC       TBK1 thereby suppressing the interferon signaling (By similarity). Part
CC       of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and
CC       the RNA-directed RNA polymerase embedded in an ER-derived membranous
CC       web (By similarity). {ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- SUBUNIT: [Non-structural protein 5A]: Monomer. Homodimer; dimerization
CC       is required for RNA-binding (By similarity). Interacts with the mature
CC       core protein (By similarity). Interacts (via N-terminus) with non-
CC       structural protein 4A (By similarity). Interacts with non-structural
CC       protein 4B. Interacts (via region D2) with RNA-directed RNA polymerase
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). 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). Interacts with host GRB2 (By
CC       similarity). Interacts with host BIN1 (By similarity). Interacts with
CC       host PIK3R1 (By similarity). Interacts with host SRCAP (By similarity).
CC       Interacts with host FKBP8 (By similarity). Interacts (via C-terminus)
CC       with host VAPB (via MSP domain). Interacts with host EIF2AK2/PKR; this
CC       interaction leads to disruption of EIF2AK2 dimerization by NS5A and
CC       probably allows the virus to evade the innate immune response.
CC       Interacts (via N-terminus) with host PACSIN2 (via N-terminus); this
CC       interaction attenuates protein kinase C alpha-mediated phosphorylation
CC       of PACSIN2 by disrupting the interaction between PACSIN2 and PRKCA (By
CC       similarity). Interacts (via N-terminus) with host SRC kinase (via SH2
CC       domain) (By similarity). Interacts with most Src-family kinases (By
CC       similarity). Interacts with host IFI27 and SKP2; promotes the
CC       ubiquitin-mediated proteasomal degradation of NS5A (By similarity).
CC       Interacts with host GPS2 (By similarity). Interacts with host TNFRSF21;
CC       this interaction allows the modulation by the virus of JNK, p38 MAPK,
CC       STAT3, and Akt signaling pathways in a DR6-dependent manner. Interacts
CC       (via N-terminus) with host CIDEB (via N-terminus); this interaction
CC       seems to regulate the association of HCV particles with APOE (By
CC       similarity). Interacts with host CHKA/Choline Kinase-alpha; CHKA
CC       bridges host PI4KA and NS5A and potentiates NS5A-stimulated PI4KA
CC       activity, which then facilitates the targeting of the ternary complex
CC       to the ER for viral replication (By similarity). Interacts with host
CC       SPSB2 (via C-terminus); this interaction targets NS5A for
CC       ubiquitination and degradation (By similarity). Interacts with host
CC       RAB18; this interaction may promote the association of NS5A and other
CC       replicase components with lipid droplets (By similarity). Interacts
CC       (via region D2) with host PPIA/CYPA; the interaction stimulates RNA-
CC       binding ability of NS5A and is dependent on the peptidyl-prolyl cis-
CC       trans isomerase activity of PPIA/CYPA. Interacts with host TRIM14; this
CC       interaction induces the degradation of NS5A (By similarity).
CC       {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P26663,
CC       ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
CC       ECO:0000250|UniProtKB:Q99IB8}.
CC   -!- SUBUNIT: [RNA-directed RNA polymerase]: Homooligomer (By similarity).
CC       Interacts with non-structural protein 5A (By similarity). Interacts
CC       with host VAPB (By similarity). Interacts with host PRK2/PKN2 (By
CC       similarity). Interacts with host HNRNPA1 and SEPT6; these interactions
CC       facilitate viral replication (By similarity). Part of the replication
CC       complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA
CC       polymerase (By similarity). {ECO:0000250|UniProtKB:P27958}.
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:Q99IB8}. Host nucleus
CC       {ECO:0000250|UniProtKB:P26662}. Host lipid droplet
CC       {ECO:0000250|UniProtKB:Q99IB8}. 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 (By similarity).
CC       {ECO:0000250|UniProtKB:P27958}.
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 (By similarity). HVR1 is
CC       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:P26663, ECO:0000250|UniProtKB:P27958}.
CC   -!- DOMAIN: [Protease NS2]: The N-terminus of NS3 is required for the
CC       catalytic activity of protease NS2 (By similarity). The minimal
CC       catalytic region includes the C-terminus of NS2 and the N-terminus NS3
CC       protease domain (active region NS2-3) (By similarity).
CC       {ECO:0000250|UniProtKB:P26663}.
CC   -!- DOMAIN: [Serine protease/helicase NS3]: The N-terminal one-third
CC       contains the protease activity (By similarity). This region contains a
CC       zinc atom that does not belong to the active site, but may play a
CC       structural rather than a catalytic role (By similarity). This region is
CC       essential for the activity of protease NS2, maybe by contributing to
CC       the folding of the latter (By similarity). The NTPase/helicase activity
CC       is located in the twothirds C-terminus of NS3, this domain contains the
CC       NTPase and RNA-binding regions (By similarity).
CC       {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P27958}.
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 (By similarity). The C-terminus of NS5A contains a
CC       variable region called variable region 3 (V3) (By similarity). ISDR and
CC       V3 may be involved in sensitivity and/or resistance to IFN-alpha
CC       therapy (By similarity). The C-terminus contains a nuclear localization
CC       signal (By similarity). The SH3-binding domain is involved in the
CC       interaction with host BIN1, GRB2 and Src-family kinases (By
CC       similarity). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000250|UniProtKB:P27958}.
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 (By similarity). Cleavage by the signal peptidase releases the
CC       21 kDa mature core protein (By similarity). The cleavage of the core
CC       protein precursor occurs between aminoacids 176 and 188 but the exact
CC       cleavage site is not known (By similarity). Some degraded forms of the
CC       core protein appear as well during the course of infection (By
CC       similarity). The other proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and
CC       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       (By similarity). {ECO:0000250|UniProtKB:P26664,
CC       ECO:0000250|UniProtKB:P27958}.
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 (By similarity). 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 (By
CC       similarity). {ECO:0000250|UniProtKB:P26662,
CC       ECO:0000250|UniProtKB:P26664}.
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; Y11604; CAA72338.1; -; Genomic_RNA.
DR   PIR; PQ0804; PQ0804.
DR   RefSeq; YP_001469632.1; NC_009825.1.
DR   PDB; 6P6Z; X-ray; 2.29 A; A=1030-1208, A=1678-1688.
DR   PDBsum; 6P6Z; -.
DR   BMRB; O39929; -.
DR   SMR; O39929; -.
DR   BindingDB; O39929; -.
DR   DrugCentral; O39929; -.
DR   MEROPS; C18.001; -.
DR   MEROPS; S29.001; -.
DR   GeneID; 11027168; -.
DR   KEGG; vg:11027168; -.
DR   euHCVdb; Y11604; -.
DR   BRENDA; 3.4.21.98; 17004.
DR   Proteomes; UP000007415; Genome.
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; cd20903; HCV_p7; 1.
DR   CDD; cd23202; Hepacivirus_RdRp; 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; 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; 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; Disulfide bond;
KW   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..3008
FT                   /note="Genome polyprotein"
FT                   /id="PRO_0000450900"
FT   CHAIN           2..191
FT                   /note="Core protein precursor"
FT                   /id="PRO_0000045532"
FT   CHAIN           2..177
FT                   /note="Mature core protein"
FT                   /id="PRO_0000045533"
FT   PROPEP          178..191
FT                   /note="ER anchor for the core protein, removed in mature
FT                   form by host signal peptidase"
FT                   /id="PRO_0000045534"
FT   CHAIN           192..383
FT                   /note="Envelope glycoprotein E1"
FT                   /id="PRO_0000045535"
FT   CHAIN           384..746
FT                   /note="Envelope glycoprotein E2"
FT                   /id="PRO_0000045536"
FT   CHAIN           747..809
FT                   /note="Viroporin p7"
FT                   /id="PRO_0000045537"
FT   CHAIN           810..1026
FT                   /note="Protease NS2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT                   /id="PRO_0000045538"
FT   CHAIN           1027..1657
FT                   /note="Serine protease/helicase NS3"
FT                   /id="PRO_0000045539"
FT   CHAIN           1658..1711
FT                   /note="Non-structural protein 4A"
FT                   /id="PRO_0000045540"
FT   CHAIN           1712..1972
FT                   /note="Non-structural protein 4B"
FT                   /id="PRO_0000045541"
FT   CHAIN           1973..2417
FT                   /note="Non-structural protein 5A"
FT                   /id="PRO_0000045542"
FT   CHAIN           2418..3008
FT                   /note="RNA-directed RNA polymerase"
FT                   /id="PRO_0000045543"
FT   TOPO_DOM        2..168
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        169..189
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
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..782
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        783..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..881
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TRANSMEM        882..902
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TOPO_DOM        903..928
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TRANSMEM        929..949
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   TOPO_DOM        950..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:0000250|UniProtKB:P27958"
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..2002
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TOPO_DOM        2003..2987
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   TRANSMEM        2988..3008
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          2631..2749
FT                   /note="RdRp catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT   REGION          2..75
FT                   /note="Disordered"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
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..412
FT                   /note="HVR1"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          475..479
FT                   /note="HVR2"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          481..494
FT                   /note="CD81-binding 1"
FT                   /evidence="ECO:0000250|UniProtKB:P26663"
FT   REGION          545..552
FT                   /note="CD81-binding 2"
FT                   /evidence="ECO:0000250|UniProtKB:P26663"
FT   REGION          660..671
FT                   /note="PKR/eIF2-alpha phosphorylation homology domain
FT                   (PePHD)"
FT                   /evidence="ECO:0000250"
FT   REGION          904..1206
FT                   /note="Protease NS2-3"
FT                   /evidence="ECO:0000250|UniProtKB:P26663"
FT   REGION          929..949
FT                   /note="Interaction with host SCPS1"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   REGION          1486..1498
FT                   /note="RNA-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P26663"
FT   REGION          1679..1690
FT                   /note="NS3-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          2120..2329
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..2435
FT                   /note="Interaction with host SKP2"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   REGION          2210..2272
FT                   /note="Interaction with EIF2AK2/PKR"
FT                   /evidence="ECO:0000250|UniProtKB:P26663"
FT   REGION          2210..2245
FT                   /note="ISDR"
FT                   /evidence="ECO:0000250|UniProtKB:P26662"
FT   REGION          2245..2303
FT                   /note="NS4B-binding"
FT                   /evidence="ECO:0000255"
FT   REGION          2296..2373
FT                   /note="V3"
FT   REGION          2346..2406
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
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           2319..2322
FT                   /note="SH3-binding"
FT                   /evidence="ECO:0000255"
FT   MOTIF           2324..2332
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        2349..2373
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   ACT_SITE        1107
FT                   /note="Charge relay system; for serine protease NS3
FT                   activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT   ACT_SITE        1165
FT                   /note="Charge relay system; for serine protease NS3
FT                   activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
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   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   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   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   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         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         2637
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:0000250|UniProtKB:P26663"
FT   BINDING         2735
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:0000250|UniProtKB:P26663"
FT   BINDING         2736
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:0000250|UniProtKB:P26663"
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   SITE            809..810
FT                   /note="Cleavage; by host signal peptidase"
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 NS3"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   SITE            1711..1712
FT                   /note="Cleavage; by serine protease NS3"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   SITE            1972..1973
FT                   /note="Cleavage; by serine protease NS3"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   SITE            2417..2418
FT                   /note="Cleavage; by serine protease 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"
FT                   /evidence="ECO:0000250|UniProtKB:Q01403"
FT   MOD_RES         2194
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   MOD_RES         2197
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   MOD_RES         2201
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   MOD_RES         2204
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT   MOD_RES         2207
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q99IB8"
FT   MOD_RES         2446
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           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:0000250|UniProtKB:P27958"
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        305
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   CARBOHYD        417
FT                   /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT                   host"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
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...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        476
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        533
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        557
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
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..553
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        452..459
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        487..495
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        504..509
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   DISULFID        565..570
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        2347
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:P27958"
FT   STRAND          1058..1063
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1068..1074
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1077..1081
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   HELIX           1082..1085
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1100..1103
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   TURN            1104..1107
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1108..1112
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1128..1133
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1139..1144
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1146..1157
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   HELIX           1158..1161
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1168..1170
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1176..1186
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   STRAND          1189..1197
FT                   /evidence="ECO:0007829|PDB:6P6Z"
FT   HELIX           1198..1200
FT                   /evidence="ECO:0007829|PDB:6P6Z"
SQ   SEQUENCE   3008 AA;  327599 MW;  8E7FC932E27C406F CRC64;
     MSTNPKPQRK TKRNTNRRPM DVKFPGGGQI VGGVYLLPRR GPRLGVRATR KTSERSQPRG
     RRQPIPKARR PEGRSWAQPG YPWPLYGNEG CGWAGWLLSP RGSRPSWGPN DPRGRSRNLG
     KVIDTLTCGF ADLMGYIPLV GAPVGSVARA LAHGVRALED GINYATGNLP GCSFSIFLLA
     LLSCLTVPAS AVNYRNVSGI YHVTNDCPNS SIVYEADHHI MHLPGCVPCV REGNQSRCWV
     ALTPTVAAPY IGAPLESLRS HVDLMVGAAT VCSGLYIGDL CGGLFLVGQM FSFRPRRHWT
     TQDCNCSIYT GHITGHRMAW DMMMNWSPTT TLVLAQVMRI PTTLVDLLSG GHWGVLVGVA
     YFSMQANWAK VILVLFLFAG VDAETHVSGA AVGRSTAGLA NLFSSGSKQN LQLINSNGSW
     HINRTALNCN DSLNTGFLAS LFYTHKFNSS GCSERLACCK SLDSYGQGWG PLGVANISGS
     SDDRPYCWHY APRPCGIVPA SSVCGPVYCF TPSPVVVGTT DHVGVPTYTW GENETDVFLL
     NSTRPPHGAW FGCVWMNSTG FTKTCGAPPC EVNTNNGTWH CPTDCFRKHP ETTYAKCGSG
     PWITPRCLID YPYRLWHFPC TANFSVFNIR TFVGGIEHRM QAACNWTRGE VCGLEHRDRV
     ELSPLLLTTT AWQILPCSFT TLPALSTGLI HLHQNIVDVQ YLYGVGSAVV SWALKWEYVV
     LAFLLLADAR VSAYLWMMFM VSQVEAALSN LININAASAA GAQGFWYAIL FICIVWHVKG
     RFPAAAAYAA CGLWPCFLLL LMLPERAYAY DQEVAGSLGG AIVVMLTILT LSPHYKLWLA
     RGLWWIQYFI ARTEAVLHVY IPSFNVRGPR DSVIVLAVLV CPDLVFDITK YLLAILGPLH
     ILQASLLRIP YFVRAQALVK ICSLLRGVVY GKYFQMVVLK SRGLTGTYIY DHLTPMSDWP
     PYGLRDLAVA LEPVVFTPME KKVIVWGADT AACGDIIRGL PVSARLGNEI LLGPADTETS
     KGWRLLAPIT AYAQQTRGLF STIVTSLTGR DTNENCGEVQ VLSTATQSFL GTAVNGVMWT
     VYHGAGAKTI SGPKGPVNQM YTNVDQDLVG WPAPPGVRSL APCTCGSADL YLVTRHADVI
     PVRRRGDTRG ALLSPRPISI LKGSSGGPLL CPMGHRAGIF RAAVCTRGVA KAVDFVPVES
     LETTMRSPVF TDNSTPPAVP QTYQVAHLHA PTGSGKSTKV PAAHAAQGYK VLVLNPSVAA
     TLGFGVYMSK AYGIDPNIRS GVRTITTGAP ITYSTYGKFL ADGGCSGGAY DIIICDECYS
     TDSTTILGIG TVLDQAETAG VRLTVLATAT PPGSVTTPHS NIEEVALPTT GEIPFYGKAI
     PLELIKGGRH LIFCHSKKKC DELARQLTSL GLNAVAYYRG LDVSVIPTSG DVVVCATDAL
     MTGFTGDFDS VIDCNTSVIQ TVDFSLDPTF SIEITTVPQD AVSRSQRRGR TGRGRLGTYR
     YVTPGERPSG MFDTAELCEC YDAGCAWYEL TPAETTTRLK AYFDTPGLPV CQDHLEFWES
     VFTGLTHIDG HFLSQTKQSG ENFPYLVAYQ ATVSAKVWLA PPSWDTMWKC LIRLKPTLHG
     PTPLLYRLGS VQNEVVLTHP ITKYIMACMS ADLEVVTSTW VLVGGVLAAL AAYCLSVGSV
     VIVGRVVLSG QPAVIPDREV LYQQFDEMEE CSKHLPLVEH GLQLAEQFKQ KALGLLNFAG
     KQAQEATPVI QSNFAKLEQF WANDMWNFIS GIQYLAGLST LPGNPAIASL MSFTAAVTSP
     LTTQQTLLFN ILGGWVASQI RDSDASTAFV VSGLAGAAVG SVGLGKILVD ILPGYGAGVR
     GAVVTFKIMS GEMPSTEDLV NLLPAILSPG ALVVEVVCPA ILRRHVGPGE GAVQWMNRLI
     AFASRGNHVS PTHYVPESDA ARRVTTILSS LTVTSLLRRL HKWINEDCST PCAESWLWEV
     WDWVLHVLSD FKTCLKAKFV PLMPGIPLLS WPRGYKGEWR GDGVMHTTCP CGADLAGHIK
     NGSMRITGPK TCSNTWHGTF PINAYTTGPG VPIPAPNYKF ALWRVSAEDY VEVRRVGDFH
     YVTGVTQDNI KFPCQVPAPE LFTEVDGIRI HRHAPKCKPL LRDEVSFSVG LNSFVVGSQL
     PCEPEPDVAV LTSMLTDPSH ITAESARRRL ARGSRPSLAS SSASQLSPRL LQATCTAPHD
     SPGTDLLEAN LLWGSTATRV ETDEKVIILD SFESCVAEQN DDREVSVAAE ILRPTKKFPP
     ALPIWARPDY NPPLTETWKQ QDYQAPTVHG CALPPAKQPP VPSPRRKRTV QLTESVVSTA
     LAELAAKTFG QSEPSSDRDT DLTTPTETTD SGPIVVDDAS DDGSYSSMPP LEGEPGDPDL
     TSDSWSTVSG SEDVVCCSMS YSWTGALVTP CAAEESKLPI SPLSNSLLRH HNMVYATTTR
     SAVTRQKKVT FDRLQVVDST YNEVLKEIKA RASRVKPRLL TTEEACDLTP PHSARSKFGY
     GKKDVRSHSR KAINHISSVW KDLLDDNNTP IPTTIMAKNE VFAVNPAKGG RKPARLIVYP
     DLGSRVCEKR ALHDVIKKTA LAVMGAAYGF QYSPAQRVEF LLTAWKSKND PMGFSYDTRC
     FDSTVTEKDI RVEEEVYQCC DLEPEARKVI TALTDRLYVG GPMHNSKGDL CGYRRCRATG
     VYTTSFGNTL TCYLKATAAI RAAALRDCTM LVCGDDLVVI AESDGVEEDN RALRAFTEAM
     TRYSAPPGDA PQPAYDLELI TSCSSNVSVA HDVTGKKVYY LTRDPETPLA RAVWETVRHT
     PVNSWLGNII VYAPTIWVRM ILMTHFFSIL QSQEALEKAL DFDMYGVTYS ITPLDLPAII
     QRLHGLSAFT LHGYSPHELN RVAGALRKLG VPPLRAWRHR ARAVRAKLIA QGGRAKICGI
     YLFNWAVKTK LKLTPLPAAA KLDLSGWFTV GAGGGDIYHS MSHARPRYLL LCLLILTVGV
     GIFLLPAR
//