POLG_HCVJF
ID POLG_HCVJF Reviewed; 3033 AA.
AC Q99IB8;
DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 174.
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:0000269|PubMed:29070684, ECO:0000269|PubMed:30281972};
DE EC=3.6.4.13 {ECO:0000269|PubMed:29070684, ECO:0000269|PubMed:30281972};
DE AltName: Full=Hepacivirin;
DE AltName: Full=NS3 helicase {ECO:0000303|PubMed:29070684};
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 2a (isolate JFH-1) (HCV).
OC Viruses; Riboviria; Orthornavirae; Kitrinoviricota; Flasuviricetes;
OC Amarillovirales; Flaviviridae; Hepacivirus.
OX NCBI_TaxID=356411;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=11424123; DOI=10.1002/jmv.1055;
RA Kato T., Furusaka A., Miyamoto M., Date T., Yasui K., Hiramoto J.,
RA Nagayama K., Tanaka T., Wakita T.;
RT "Sequence analysis of hepatitis C virus isolated from a fulminant hepatitis
RT patient.";
RL J. Med. Virol. 64:334-339(2001).
RN [2]
RP SUBCELLULAR LOCATION (VIROPORIN P7).
RX PubMed=17170445; DOI=10.1099/vir.0.82049-0;
RA Haqshenas G., Mackenzie J.M., Dong X., Gowans E.J.;
RT "Hepatitis C virus p7 protein is localized in the endoplasmic reticulum
RT when it is encoded by a replication-competent genome.";
RL J. Gen. Virol. 88:134-142(2007).
RN [3]
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 [4]
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 [5]
RP INTERACTION WITH NON-STRUCTURAL PROTEIN 5A (MATURE CORE PROTEIN),
RP INTERACTION WITH MATURE CORE PROTEIN (NON-STRUCTURAL PROTEIN 5A), FUNCTION
RP (NON-STRUCTURAL PROTEIN 5A), FUNCTION (MATURE CORE PROTEIN), AND
RP MUTAGENESIS OF 2428-SER--SER-2433.
RX PubMed=18524832; DOI=10.1128/jvi.00826-08;
RA Masaki T., Suzuki R., Murakami K., Aizaki H., Ishii K., Murayama A.,
RA Date T., Matsuura Y., Miyamura T., Wakita T., Suzuki T.;
RT "Interaction of hepatitis C virus nonstructural protein 5A with core
RT protein is critical for the production of infectious virus particles.";
RL J. Virol. 82:7964-7976(2008).
RN [6]
RP FUNCTION (ENVELOPE GLYCOPROTEIN E1), AND FUNCTION (ENVELOPE GLYCOPROTEIN
RP E2).
RX PubMed=17325668; DOI=10.1038/nature05654;
RA Evans M.J., von Hahn T., Tscherne D.M., Syder A.J., Panis M., Wolk B.,
RA Hatziioannou T., McKeating J.A., Bieniasz P.D., Rice C.M.;
RT "Claudin-1 is a hepatitis C virus co-receptor required for a late step in
RT entry.";
RL Nature 446:801-805(2007).
RN [7]
RP FUNCTION (NON-STRUCTURAL PROTEIN 5A), AND RNA-BINDING (NON-STRUCTURAL
RP PROTEIN 5A).
RX PubMed=20592076; DOI=10.1128/jvi.00616-10;
RA Foster T.L., Belyaeva T., Stonehouse N.J., Pearson A.R., Harris M.;
RT "All three domains of the hepatitis C virus nonstructural NS5A protein
RT contribute to RNA binding.";
RL J. Virol. 84:9267-9277(2010).
RN [8]
RP INTERACTION WITH HUMAN PPIA (NON-STRUCTURAL PROTEIN 5A), MUTAGENESIS OF
RP ASP-2292 AND TYR-2293, AND DOMAIN (NON-STRUCTURAL PROTEIN 5A).
RX PubMed=21593166; DOI=10.1128/jvi.00393-11;
RA Foster T.L., Gallay P., Stonehouse N.J., Harris M.;
RT "Cyclophilin A interacts with domain II of hepatitis C virus NS5A and
RT stimulates RNA binding in an isomerase-dependent manner.";
RL J. Virol. 85:7460-7464(2011).
RN [9]
RP FUNCTION (PROTEASE NS2), INTERACTION WITH VIROPORIN P7 (PROTEASE NS2),
RP INTERACTION WITH PROTEASE NS2 (VIROPORIN P7), INTERACTION WITH ENVELOPE
RP GLYCOPROTEIN E2 (PROTEASE NS2), INTERACTION WITH PROTEASE NS2 (ENVELOPE
RP GLYCOPROTEIN E2), AND SUBCELLULAR LOCATION (PROTEASE NS2).
RX PubMed=21347350; DOI=10.1371/journal.ppat.1001278;
RA Popescu C.I., Callens N., Trinel D., Roingeard P., Moradpour D.,
RA Descamps V., Duverlie G., Penin F., Heliot L., Rouille Y., Dubuisson J.;
RT "NS2 protein of hepatitis C virus interacts with structural and non-
RT structural proteins towards virus assembly.";
RL PLoS Pathog. 7:e1001278-e1001278(2011).
RN [10]
RP INTERACTION WITH HOST PLA2G4C (NON-STRUCTURAL PROTEIN 4B), AND SUBCELLULAR
RP LOCATION (NON-STRUCTURAL PROTEIN 4B).
RX PubMed=23015700; DOI=10.1128/jvi.01785-12;
RA Xu S., Pei R., Guo M., Han Q., Lai J., Wang Y., Wu C., Zhou Y., Lu M.,
RA Chen X.;
RT "Cytosolic phospholipase A2 gamma is involved in hepatitis C virus
RT replication and assembly.";
RL J. Virol. 86:13025-13037(2012).
RN [11]
RP INTERACTION WITH HOST GPS2 (NON-STRUCTURAL PROTEIN 5A).
RX PubMed=24223774; DOI=10.1371/journal.pone.0078195;
RA Xu G., Xin X., Zheng C.;
RT "GPS2 is required for the association of NS5A with VAP-A and hepatitis C
RT virus replication.";
RL PLoS ONE 8:E78195-E78195(2013).
RN [12]
RP INTERACTION WITH HOST SPCS1 (ENVELOPE GLYCOPROTEIN E2), AND INTERACTION
RP WITH HOST SPCS1 (PROTEASE NS2).
RX PubMed=24009510; DOI=10.1371/journal.ppat.1003589;
RA Suzuki R., Matsuda M., Watashi K., Aizaki H., Matsuura Y., Wakita T.,
RA Suzuki T.;
RT "Signal peptidase complex subunit 1 participates in the assembly of
RT hepatitis C virus through an interaction with E2 and NS2.";
RL PLoS Pathog. 9:E1003589-E1003589(2013).
RN [13]
RP PROTEOLYTIC CLEAVAGE (GENOME POLYPROTEIN), AND SUBCELLULAR LOCATION (MATURE
RP CORE PROTEIN).
RX PubMed=23543610; DOI=10.1007/s12250-013-3296-7;
RA Liao Q., Tian J., Wu Y., Chen X.;
RT "The identification of three sizes of core proteins during the
RT establishment of persistent hepatitis C virus infection in vitro.";
RL Virol. Sin. 28:129-135(2013).
RN [14]
RP SUBCELLULAR LOCATION (MATURE CORE PROTEIN), AND NUCLEAR LOCALIZATION SIGNAL
RP (MATURE CORE PROTEIN).
RX PubMed=25485706; DOI=10.1371/journal.pone.0114629;
RA Levin A., Neufeldt C.J., Pang D., Wilson K., Loewen-Dobler D., Joyce M.A.,
RA Wozniak R.W., Tyrrell D.L.;
RT "Functional characterization of nuclear localization and export signals in
RT hepatitis C virus proteins and their role in the membranous web.";
RL PLoS ONE 9:e114629-e114629(2014).
RN [15]
RP PHOSPHORYLATION AT SER-2198; SER-2211 AND THR-2324, AND MUTAGENESIS OF
RP SER-2211.
RX PubMed=26874015; DOI=10.1016/j.virol.2016.01.018;
RA Eyre N.S., Hampton-Smith R.J., Aloia A.L., Eddes J.S., Simpson K.J.,
RA Hoffmann P., Beard M.R.;
RT "Phosphorylation of NS5A Serine-235 is essential to hepatitis C virus RNA
RT replication and normal replication compartment formation.";
RL Virology 491:27-44(2016).
RN [16]
RP PHOSPHORYLATION AT SER-2198; SER-2208 AND SER-2211, AND MUTAGENESIS OF
RP SER-2208 AND SER-2211.
RX PubMed=28446668; DOI=10.1128/jvi.00194-17;
RA Hsu S.C., Lo C.W., Pan T.C., Lee K.Y., Yu M.J.;
RT "Serine 235 Is the Primary NS5A Hyperphosphorylation Site Responsible for
RT Hepatitis C Virus Replication.";
RL J. Virol. 91:0-0(2017).
RN [17]
RP FUNCTION (VIROPORIN P7), AND TOPOLOGY (VIROPORIN P7).
RX PubMed=29253880; DOI=10.1371/journal.ppat.1006774;
RA Denolly S., Mialon C., Bourlet T., Amirache F., Penin F., Lindenbach B.,
RA Boson B., Cosset F.L.;
RT "The amino-terminus of the hepatitis C virus (HCV) p7 viroporin and its
RT cleavage from glycoprotein E2-p7 precursor determine specific infectivity
RT and secretion levels of HCV particle types.";
RL PLoS Pathog. 13:e1006774-e1006774(2017).
RN [18]
RP IDENTIFICATION IN A COMPLEX WITH HOST PI4KA AND CHKA (NON-STRUCTURAL
RP PROTEIN 5A).
RX PubMed=28566381; DOI=10.1128/jvi.00355-17;
RA Wong M.T., Chen S.S.;
RT "Hepatitis C Virus Subverts Human Choline Kinase-alpha To Bridge
RT Phosphatidylinositol-4-Kinase IIIalpha (PI4KIIIalpha) and NS5A and
RT Upregulates PI4KIIIalpha Activation, Thereby Promoting the Translocation of
RT the Ternary Complex to the Endoplasmic Reticulum for Viral Replication.";
RL J. Virol. 91:0-0(2017).
RN [19]
RP DOMAIN (NON-STRUCTURAL PROTEIN 5A), AND INTERACTION WITH RNA-DIRECTED RNA
RP POLYMERASE.
RX PubMed=28912275; DOI=10.1074/jbc.m117.813766;
RA Bessa L.M., Launay H., Dujardin M., Cantrelle F.X., Lippens G.,
RA Landrieu I., Schneider R., Hanoulle X.;
RT "NMR reveals the intrinsically disordered domain 2 of NS5A protein as an
RT allosteric regulator of the hepatitis C virus RNA polymerase NS5B.";
RL J. Biol. Chem. 292:18024-18043(2017).
RN [20]
RP PHOSPHORYLATION AT SER-2205; SER-2208 AND SER-2211, AND MUTAGENESIS OF
RP SER-2205; SER-2208 AND SER-2211.
RX PubMed=30089697; DOI=10.1128/jvi.01295-18;
RA Hsu S.C., Tsai C.N., Lee K.Y., Pan T.C., Lo C.W., Yu M.J.;
RT "Sequential S232/S235/S238 Phosphorylation of the Hepatitis C Virus
RT Nonstructural Protein 5A.";
RL J. Virol. 92:0-0(2018).
RN [21]
RP FUNCTION (SERINE PROTEASE/HELICASE NS3), CATALYTIC ACTIVITY (SERINE
RP PROTEASE/HELICASE NS3), MUTAGENESIS OF CYS-1322, AND COFACTOR (SERINE
RP PROTEASE/HELICASE NS3).
RX PubMed=30281972; DOI=10.1021/acs.biochem.8b00796;
RA Yerukhimovich M.M., Marohnic C.C., Frick D.N.;
RT "Role of the Conserved DECH-Box Cysteine in Coupling Hepatitis C Virus
RT Helicase-Catalyzed ATP Hydrolysis to RNA Unwinding.";
RL Biochemistry 57:6247-6255(2018).
RN [22]
RP FUNCTION (SERINE PROTEASE/HELICASE NS3), AND CATALYTIC ACTIVITY (SERINE
RP PROTEASE/HELICASE NS3).
RX PubMed=29070684; DOI=10.1128/jvi.01253-17;
RA Zhou T., Ren X., Adams R.L., Pyle A.M.;
RT "NS3 from Hepatitis C Virus Strain JFH-1 Is an Unusually Robust Helicase
RT That Is Primed To Bind and Unwind Viral RNA.";
RL J. Virol. 92:0-0(2018).
RN [23]
RP INTERACTION WITH HOST RBM24 (MATURE CORE PROTEIN), AND INTERACTION WITH
RP HOST RBM24 (SERINE PROTEASE/HELICASE NS3).
RX PubMed=29380205; DOI=10.1007/s13238-018-0507-x;
RA Cao H., Zhao K., Yao Y., Guo J., Gao X., Yang Q., Guo M., Zhu W., Wang Y.,
RA Wu C., Chen J., Zhou Y., Hu X., Lu M., Chen X., Pei R.;
RT "RNA binding protein 24 regulates the translation and replication of
RT hepatitis C virus.";
RL Protein Cell 9:930-944(2018).
RN [24]
RP FUNCTION (NON-STRUCTURAL PROTEIN 4B), AND DOMAIN (NON-STRUCTURAL PROTEIN
RP 4B).
RX PubMed=29167346; DOI=10.1128/jvi.01890-17;
RA Paul D., Madan V., Ramirez O., Bencun M., Stoeck I.K., Jirasko V.,
RA Bartenschlager R.;
RT "Glycine Zipper Motifs in Hepatitis C Virus Nonstructural Protein 4B Are
RT Required for the Establishment of Viral Replication Organelles.";
RL J. Virol. 92:e01890-e01917(2018).
RN [25]
RP DOMAIN (NON-STRUCTURAL PROTEIN 5A), MUTAGENESIS OF PRO-2011; TYR-2019;
RP GLY-2021; TRP-2023; GLY-2027; CYS-2035; GLY-2036; VAL-2043; GLY-2072;
RP THR-2110 AND PRO-2121, RNA-BINDING, SUBUNIT (NON-STRUCTURAL PROTEIN 5A),
RP SUBCELLULAR LOCATION (NON-STRUCTURAL PROTEIN 5A), AND SUBCELLULAR LOCATION
RP (MATURE CORE PROTEIN).
RX PubMed=29352312; DOI=10.1371/journal.ppat.1006834;
RA Yin C., Goonawardane N., Stewart H., Harris M.;
RT "A role for domain I of the hepatitis C virus NS5A protein in virus
RT assembly.";
RL PLoS Pathog. 14:e1006834-e1006834(2018).
RN [26]
RP INTERACTION WITH HOST PPIA (NON-STRUCTURAL PROTEIN 5A), AND DOMAIN
RP (NON-STRUCTURAL PROTEIN 5A).
RX PubMed=31315928; DOI=10.1074/jbc.ra119.009537;
RA Dujardin M., Madan V., Gandhi N.S., Cantrelle F.X., Launay H., Huvent I.,
RA Bartenschlager R., Lippens G., Hanoulle X.;
RT "Cyclophilin A allows the allosteric regulation of a structural motif in
RT the disordered domain 2 of NS5A and thereby fine-tunes HCV RNA
RT replication.";
RL J. Biol. Chem. 294:13171-13185(2019).
RN [27]
RP FUNCTION (NON-STRUCTURAL PROTEIN 5A), PHOSPHORYLATION (NON-STRUCTURAL
RP PROTEIN 5A), PHOSPHORYLATION AT SER-2205; SER-2208; SER-2211 AND SER-2214,
RP AND MUTAGENESIS OF SER-2211.
RX PubMed=31511391; DOI=10.1128/jvi.01028-19;
RA Tsai C.N., Pan T.C., Chiang C.H., Yu C.C., Su S.H., Yu M.J.;
RT "Serine 229 Balances the Hepatitis C Virus Nonstructural Protein NS5A
RT between Hypo- and Hyperphosphorylated States.";
RL J. Virol. 93:0-0(2019).
RN [28]
RP PHOSPHORYLATION AT TYR-2069, AND INTERACTION WITH HOST SRC (NON-STRUCTURAL
RP PROTEIN 5A).
RX PubMed=30862675; DOI=10.1074/jbc.ra119.007656;
RA Klinker S., Stindt S., Gremer L., Bode J.G., Gertzen C.G.W., Gohlke H.,
RA Weiergraeber O.H., Hoffmann S., Willbold D.;
RT "Phosphorylated tyrosine 93 of hepatitis C virus nonstructural protein 5A
RT is essential for interaction with host c-Src and efficient viral
RT replication.";
RL J. Biol. Chem. 294:7388-7402(2019).
RN [29]
RP FUNCTION (PROTEASE NS2), IDENTIFICATION IN THE ASSEMBLY INITIATION COMPLEX
RP (PROTEASE NS2), IDENTIFICATION IN THE ASSEMBLY INITIATION COMPLEX (ENVELOPE
RP GLYCOPROTEIN E1), IDENTIFICATION IN THE ASSEMBLY INITIATION COMPLEX
RP (ENVELOPE GLYCOPROTEIN E2), IDENTIFICATION IN THE ASSEMBLY INITIATION
RP COMPLEX (SERINE PROTEASE/HELICASE NS3), IDENTIFICATION IN THE ASSEMBLY
RP INITIATION COMPLEX (NON-STRUCTURAL PROTEIN 4A), IDENTIFICATION IN THE
RP ASSEMBLY INITIATION COMPLEX (NON-STRUCTURAL PROTEIN 5A), AND IDENTIFICATION
RP IN THE ASSEMBLY INITIATION COMPLEX (MATURE CORE PROTEIN).
RX PubMed=31121874; DOI=10.3390/cells8050487;
RA Boyer A., Dreneau J., Dumans A., Burlaud-Gaillard J., Bull-Maurer A.,
RA Roingeard P., Meunier J.C.;
RT "Endoplasmic Reticulum Detergent-Resistant Membranes Accommodate Hepatitis
RT C Virus Proteins for Viral Assembly.";
RL Cells 8:0-0(2019).
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 (PubMed:18524832). 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 NF-kappa-B activation,
CC and activates AP-1 (By similarity). Binds to dendritic cells (DCs) via
CC C1QR1, resulting in down-regulation of T-lymphocytes proliferation (By
CC similarity). Alters lipid metabolism by interacting with hepatocellular
CC proteins involved in lipid accumulation and storage (By similarity).
CC Induces up-regulation of FAS promoter activity, and thereby contributes
CC to the increased triglyceride accumulation in hepatocytes (steatosis)
CC (By similarity). {ECO:0000250|UniProtKB:P26662,
CC ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
CC ECO:0000250|UniProtKB:P29846, ECO:0000269|PubMed:18524832,
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) (PubMed:17325668). {ECO:0000250|UniProtKB:P27958,
CC ECO:0000269|PubMed:17325668}.
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) (PubMed:17325668). Inhibits
CC host EIF2AK2/PKR activation, preventing the establishment of an
CC antiviral state (By similarity). Viral ligand for CD209/DC-SIGN and
CC CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs),
CC and on liver sinusoidal endothelial cells and macrophage-like cells of
CC lymph node sinuses (By similarity). These interactions allow the
CC capture of circulating HCV particles by these cells and subsequent
CC facilitated transmission to permissive cells such as hepatocytes and
CC lymphocyte subpopulations (By similarity). The interaction between E2
CC and host amino acid transporter complex formed by SLC3A2 and
CC SLC7A5/LAT1 may facilitate viral entry into host cell (By similarity).
CC {ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
CC ECO:0000269|PubMed:17325668}.
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 (PubMed:29253880). Regulates the host cell secretory
CC pathway, which induces the intracellular retention of viral
CC glycoproteins and favors assembly of viral particles (PubMed:29253880).
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:0000269|PubMed:29253880, 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 (PubMed:31121874,
CC PubMed:21347350). {ECO:0000250|UniProtKB:P26663,
CC ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:21347350,
CC ECO:0000269|PubMed:31121874}.
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 (PubMed:29070684). Binds a single ATP and catalyzes the
CC unzipping of a single base pair of dsRNA (By similarity). Inhibits host
CC antiviral proteins TBK1 and IRF3 thereby preventing the establishment
CC of an 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:29070684}.
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 (PubMed:29167346). This membrane alteration gives rise to the so-called
CC ER-derived membranous web that contains the replication complex
CC (PubMed:29167346). NS4B self-interaction contributes to its function in
CC membranous web formation (PubMed:29167346). 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 ECO:0000269|PubMed:29167346}.
CC -!- FUNCTION: [Non-structural protein 5A]: Phosphorylated protein that is
CC indispensable for viral replication and assembly (PubMed:31511391).
CC Both hypo- and hyperphosphorylated states are required for the viral
CC life cycle (PubMed:31511391). The hyperphosphorylated form of NS5A is
CC an inhibitor of viral replication (By similarity). Involved in RNA-
CC binding and especially in binding to the viral genome
CC (PubMed:20592076). Zinc is essential for RNA-binding (By similarity).
CC Participates in the viral particle production as a result of its
CC interaction with the viral mature core protein (PubMed:18524832). Its
CC interaction with host VAPB may target the viral replication complex to
CC vesicles (By similarity). Down-regulates viral IRES translation
CC initiation (By similarity). Mediates interferon resistance, presumably
CC by interacting with and inhibiting host EIF2AK2/PKR (By similarity).
CC Prevents BIN1-induced apoptosis (By similarity). Acts as a
CC transcriptional activator of some host genes important for viral
CC replication when localized in the nucleus (By similarity)
CC (PubMed:30281972). Via the interaction with host PACSIN2, modulates
CC lipid droplet formation in order to promote virion assembly (By
CC similarity). Modulates TNFRSF21/DR6 signaling pathway for viral
CC propagation (By similarity). {ECO:0000250|UniProtKB:P26662,
CC ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
CC ECO:0000250|UniProtKB:Q9WMX2, ECO:0000269|PubMed:18524832,
CC ECO:0000269|PubMed:20592076, ECO:0000269|PubMed:30281972,
CC ECO:0000269|PubMed:31511391}.
CC -!- FUNCTION: [RNA-directed RNA polymerase]: RNA-dependent RNA polymerase
CC that performs primer-template recognition and RNA synthesis during
CC viral replication. {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:0000269|PubMed:29070684, ECO:0000269|PubMed:30281972};
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:0000269|PubMed:29070684, ECO:0000269|PubMed:30281972};
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: 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 -!- SUBUNIT: [Mature core protein]: Homooligomer (By similarity). Interacts
CC with E1 (via C-terminus) (By similarity). Interacts with the non-
CC structural protein 5A (PubMed:18524832). Interacts (via N-terminus)
CC with 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
CC (PubMed:29380205). Interacts (via N-terminus) with host EIF2AK2/PKR
CC (via N-terminus); this interaction induces the autophosphorylation of
CC EIF2AK2 (By similarity). Part of the viral assembly initiation complex
CC composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein
CC (PubMed:31121874). {ECO:0000250|UniProtKB:P26662,
CC ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:P29846,
CC ECO:0000250|UniProtKB:Q03463, ECO:0000250|UniProtKB:Q5EG65,
CC ECO:0000269|PubMed:18524832, ECO:0000269|PubMed:29380205,
CC ECO:0000269|PubMed:31121874}.
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 (PubMed:31121874). {ECO:0000250|UniProtKB:P27958,
CC ECO:0000269|PubMed:31121874}.
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 (PubMed:24009510).
CC Interacts with protease NS2 (PubMed:21347350). 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 (PubMed:31121874). Interacts with host SLC3A2/4F2hc; the
CC interaction may facilitate viral entry into host cell (By similarity).
CC {ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:21347350,
CC ECO:0000269|PubMed:24009510, ECO:0000269|PubMed:31121874}.
CC -!- SUBUNIT: [Viroporin p7]: Homohexamer (By similarity). Homoheptamer (By
CC similarity). Interacts with protease NS2 (PubMed:21347350).
CC {ECO:0000250|UniProtKB:O92972, ECO:0000250|UniProtKB:P27958,
CC ECO:0000269|PubMed:21347350}.
CC -!- SUBUNIT: [Protease NS2]: Homodimer (By similarity). Interacts with host
CC SPCS1; this interaction is essential for viral particle assembly
CC (PubMed:24009510). Interacts with envelope glycoprotein E1 (By
CC similarity). Interacts with envelope glycoprotein E2 (PubMed:21347350).
CC Interacts with viroporin p7 (PubMed:21347350). Interacts with serine
CC protease/helicase NS3 (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 Part of the viral assembly initiation complex composed of NS2, E1, E2,
CC NS3, NS4A, NS5A and the mature core protein (PubMed:31121874).
CC {ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:21347350,
CC ECO:0000269|PubMed:24009510, ECO:0000269|PubMed:31121874}.
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 (PubMed:29380205). 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
CC (PubMed:31121874). {ECO:0000250|UniProtKB:P26663,
CC ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q9WMX2,
CC ECO:0000269|PubMed:29380205, ECO:0000269|PubMed:31121874}.
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 (PubMed:31121874). {ECO:0000250|UniProtKB:P26662,
CC ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P27958,
CC ECO:0000269|PubMed:31121874}.
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 (PubMed:23015700). Interacts
CC with host STING; this interaction disrupts the interaction between
CC STING and TBK1 thereby suppressing the interferon signaling (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). {ECO:0000250|UniProtKB:P27958,
CC ECO:0000269|PubMed:23015700}.
CC -!- SUBUNIT: [Non-structural protein 5A]: Monomer (By similarity).
CC Homodimer; dimerization is required for RNA-binding (PubMed:29352312).
CC Interacts with the mature core protein (PubMed:18524832). Interacts
CC (via N-terminus) with non-structural protein 4A (By similarity).
CC Interacts with non-structural protein 4B (By similarity). Interacts
CC (via region D2) with RNA-directed RNA polymerase (PubMed:28912275).
CC Part of the viral assembly initiation complex composed of NS2, E1, E2,
CC NS3, NS4A, NS5A and the mature core protein (PubMed:31121874). Part of
CC the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the
CC RNA-directed RNA polymerase embedded in an ER-derived membranous web
CC (By similarity). Interacts with host GRB2 (By similarity). Interacts
CC with host BIN1 (By similarity). Interacts with host PIK3R1 (By
CC similarity). Interacts with host SRCAP (By similarity). Interacts with
CC host FKBP8 (By similarity). Interacts (via C-terminus) with host VAPB
CC (via MSP domain) (By similarity). 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 (By
CC similarity). Interacts (via N-terminus) with host PACSIN2 (via N-
CC terminus); this interaction attenuates protein kinase C alpha-mediated
CC phosphorylation of PACSIN2 by disrupting the interaction between
CC PACSIN2 and PRKCA (By similarity). Interacts (via N-terminus) with host
CC SRC kinase (via SH2 domain) (PubMed:30862675). Interacts with most Src-
CC family kinases (By similarity). Interacts with host IFI27 and SKP2;
CC promotes the ubiquitin-mediated proteasomal degradation of NS5A (By
CC similarity). Interacts with host GPS2 (PubMed:24223774). Interacts with
CC host TNFRSF21; this interaction allows the modulation by the virus of
CC 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 (PubMed:28566381).
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
CC (PubMed:21593166, PubMed:31315928). {ECO:0000250|UniProtKB:P26662,
CC ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P26664,
CC ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:18524832,
CC ECO:0000269|PubMed:21593166, ECO:0000269|PubMed:24223774,
CC ECO:0000269|PubMed:28566381, ECO:0000269|PubMed:28912275,
CC ECO:0000269|PubMed:29352312, ECO:0000269|PubMed:30862675,
CC ECO:0000269|PubMed:31121874, ECO:0000269|PubMed:31315928}.
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 the viral replication (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). {ECO:0000250|UniProtKB:P26662,
CC ECO:0000250|UniProtKB:P27958}.
CC -!- INTERACTION:
CC Q99IB8; Q99IB8: -; NbExp=4; IntAct=EBI-6674379, EBI-6674379;
CC Q99IB8; O00571: DDX3X; Xeno; NbExp=9; IntAct=EBI-6674379, EBI-353779;
CC PRO_0000045592; O60260: PRKN; Xeno; NbExp=3; IntAct=EBI-6858513, EBI-716346;
CC PRO_0000045592; Q9BRP8: PYM1; Xeno; NbExp=4; IntAct=EBI-6858513, EBI-2352802;
CC PRO_0000045592; PRO_0000037576 [P27958]; Xeno; NbExp=3; IntAct=EBI-6858513, EBI-8753518;
CC PRO_0000045595; PRO_0000045596 [Q99IB8]: -; NbExp=5; IntAct=EBI-6901441, EBI-6901449;
CC PRO_0000045596; PRO_0000045601 [Q99IB8]: -; NbExp=2; IntAct=EBI-6901449, EBI-6928570;
CC PRO_0000045596; P02771: AFP; Xeno; NbExp=2; IntAct=EBI-6901449, EBI-722498;
CC PRO_0000045596; P60033: CD81; Xeno; NbExp=2; IntAct=EBI-6901449, EBI-712921;
CC PRO_0000045596; Q9Y6A9: SPCS1; Xeno; NbExp=4; IntAct=EBI-6901449, EBI-8852196;
CC PRO_0000045597; PRO_0000045598 [Q99IB8]: -; NbExp=4; IntAct=EBI-8772829, EBI-6901421;
CC PRO_0000045598; PRO_0000045595 [Q99IB8]: -; NbExp=3; IntAct=EBI-6901421, EBI-6901441;
CC PRO_0000045598; PRO_0000045596 [Q99IB8]: -; NbExp=10; IntAct=EBI-6901421, EBI-6901449;
CC PRO_0000045598; PRO_0000045599 [Q99IB8]: -; NbExp=4; IntAct=EBI-6901421, EBI-6858501;
CC PRO_0000045598; Q9Y6A9: SPCS1; Xeno; NbExp=7; IntAct=EBI-6901421, EBI-8852196;
CC PRO_0000045599; P55265: ADAR; Xeno; NbExp=3; IntAct=EBI-6858501, EBI-2462104;
CC PRO_0000045599; Q96CV9: OPTN; Xeno; NbExp=3; IntAct=EBI-6858501, EBI-748974;
CC PRO_0000045599; P05455: SSB; Xeno; NbExp=2; IntAct=EBI-6858501, EBI-358037;
CC PRO_0000045599; P36897: TGFBR1; Xeno; NbExp=5; IntAct=EBI-6858501, EBI-1027557;
CC PRO_0000045600; Q9P0L0: VAPA; Xeno; NbExp=3; IntAct=EBI-9096996, EBI-1059156;
CC PRO_0000045600; O95292: VAPB; Xeno; NbExp=2; IntAct=EBI-9096996, EBI-1188298;
CC PRO_0000045601; O43169: CYB5B; Xeno; NbExp=5; IntAct=EBI-6928570, EBI-1058710;
CC PRO_0000045601; Q86WV6: STING1; Xeno; NbExp=5; IntAct=EBI-6928570, EBI-2800345;
CC PRO_0000045602; P07355: ANXA2; Xeno; NbExp=5; IntAct=EBI-6927873, EBI-352622;
CC PRO_0000045602; O75907: DGAT1; Xeno; NbExp=2; IntAct=EBI-6927873, EBI-3906527;
CC PRO_0000045602; Q9P035: HACD3; Xeno; NbExp=2; IntAct=EBI-6927873, EBI-359013;
CC PRO_0000045602; Q16584: MAP3K11; Xeno; NbExp=5; IntAct=EBI-6927873, EBI-49961;
CC PRO_0000045602; P42356: PI4KA; Xeno; NbExp=5; IntAct=EBI-6927873, EBI-723050;
CC PRO_0000045602; P53350: PLK1; Xeno; NbExp=4; IntAct=EBI-6927873, EBI-476768;
CC PRO_0000045602; P62937: PPIA; Xeno; NbExp=2; IntAct=EBI-6927873, EBI-437708;
CC PRO_0000045602; Q9NP72: RAB18; Xeno; NbExp=5; IntAct=EBI-6927873, EBI-722247;
CC PRO_0000045602; Q9P0L0: VAPA; Xeno; NbExp=2; IntAct=EBI-6927873, EBI-1059156;
CC PRO_0000045603; PRO_0000045602 [Q99IB8]: -; NbExp=3; IntAct=EBI-6927928, EBI-6927873;
CC PRO_0000045603; P49327: FASN; Xeno; NbExp=6; IntAct=EBI-6927928, EBI-356658;
CC PRO_0000045603; P02751: FN1; Xeno; NbExp=3; IntAct=EBI-6927928, EBI-1220319;
CC PRO_0000045603; Q9H8Y8: GORASP2; Xeno; NbExp=3; IntAct=EBI-6927928, EBI-739467;
CC PRO_0000045603; P11142: HSPA8; Xeno; NbExp=3; IntAct=EBI-6927928, EBI-351896;
CC PRO_0000045603; O75592: MYCBP2; Xeno; NbExp=3; IntAct=EBI-6927928, EBI-1043774;
CC PRO_0000045603; Q02818: NUCB1; Xeno; NbExp=3; IntAct=EBI-6927928, EBI-2622179;
CC PRO_0000045603; Q13129: RLF; Xeno; NbExp=2; IntAct=EBI-6927928, EBI-958266;
CC PRO_0000045603; Q14683: SMC1A; Xeno; NbExp=3; IntAct=EBI-6927928, EBI-80690;
CC PRO_0000045603; P05455: SSB; Xeno; NbExp=2; IntAct=EBI-6927928, EBI-358037;
CC PRO_0000045603; Q9Y2W2: WBP11; Xeno; NbExp=3; IntAct=EBI-6927928, EBI-714455;
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:0000269|PubMed:23543610}. Host cytoplasm
CC {ECO:0000269|PubMed:23543610}. Host nucleus
CC {ECO:0000250|UniProtKB:P26662}. Host lipid droplet
CC {ECO:0000269|PubMed:29352312}. 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:0000269|PubMed:17170445}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:17170445}. Host mitochondrion
CC {ECO:0000250|UniProtKB:P27958}. Host cell membrane
CC {ECO:0000269|PubMed:17170445}. 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:P26664}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P26664}. Host lipid droplet
CC {ECO:0000269|PubMed:21347350}. Note=Probably present on the surface of
CC lipid droplets. {ECO:0000305|PubMed:21347350}.
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. {ECO:0000305}.
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:P27958}. Host cytoplasm
CC {ECO:0000269|PubMed:31511391}. Host nucleus
CC {ECO:0000250|UniProtKB:P26662}. Host lipid droplet
CC {ECO:0000269|PubMed:29352312}. 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: [Mature core protein]: The disordered N-terminus allows the
CC interaction with several host proteins (By similarity). This disordered
CC region also seems to play an important role in mediating RNA
CC chaperoning (By similarity). {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:P26663,
CC 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:0000269|PubMed:29167346}.
CC -!- DOMAIN: [Non-structural protein 5A]: The N-terminus acts as membrane
CC anchor (By similarity). The C-terminus contains a nuclear localization
CC signal (By similarity). {ECO:0000250|UniProtKB:P27958}.
CC -!- DOMAIN: [Non-structural protein 5A]: Contains a variable region called
CC interferon sensitivity determining region (ISDR) and a variable region
CC called variable region 3 (V3) (By similarity). ISDR and V3 may be
CC involved in sensitivity and/or resistance to IFN-alpha therapy (By
CC similarity). {ECO:0000250|UniProtKB:P26662,
CC ECO:0000250|UniProtKB:P27958}.
CC -!- DOMAIN: [Non-structural protein 5A]: The SH3-binding domain is involved
CC in the interaction with host BIN1, GRB2 and Src-family kinases.
CC {ECO:0000250|UniProtKB:P27958}.
CC -!- DOMAIN: [Non-structural protein 5A]: The structured region D1 is
CC involved in RNA-binding. {ECO:0000250|UniProtKB:P27958}.
CC -!- DOMAIN: [Non-structural protein 5A]: The first disordered region named
CC D2 interacts with several viral and host proteins (PubMed:28912275,
CC PubMed:31315928, PubMed:21593166). The largely disordered region D3
CC mediates the interaction with several host proteins and is involved in
CC virion assembly (By similarity). {ECO:0000250|UniProtKB:P27958,
CC ECO:0000269|PubMed:21593166, ECO:0000269|PubMed:28912275,
CC ECO:0000269|PubMed:31315928}.
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 is synthesized as a 23 kDa precursor
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
CC (PubMed:23543610). 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 (By similarity). {ECO:0000250|UniProtKB:P26663,
CC ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
CC ECO:0000269|PubMed:23543610}.
CC -!- PTM: [Mature core protein]: Phosphorylated by host PKC and PKA.
CC {ECO:0000250|UniProtKB:Q01403, ECO:0000305|PubMed:23543610}.
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]: Cleaved by host caspases which arec
CC probably activated by the viral infection.
CC {ECO:0000250|UniProtKB:P26662}.
CC -!- PTM: [Non-structural protein 5A]: Ubiquitinated (By similarity).
CC Ubiquitination, most probably at Lys-2350, mediated by host IFI27 and
CC SKP2 leads to proteasomal degradation, restricting viral infection (By
CC similarity). {ECO:0000250|UniProtKB:P27958}.
CC -!- PTM: [Non-structural protein 5A]: Phosphorylated on serines in a basal
CC form termed p56 (PubMed:28446668, PubMed:26874015). p58 is a
CC hyperphosphorylated form of p56 (PubMed:31511391, PubMed:30089697,
CC PubMed:28446668, PubMed:26874015). p56 and p58 coexist in the cell in
CC roughly equivalent amounts (By similarity). Hyperphosphorylation is
CC dependent on the presence of NS4A (By similarity). Host CSNK1A1/CKI-
CC alpha, PI4KA or RPS6KB1 kinases may be responsible for NS5A
CC phosphorylation (By similarity). Phosphorylated NS5A is involved in
CC viral replication (PubMed:26874015). {ECO:0000250|UniProtKB:P26662,
CC ECO:0000250|UniProtKB:P26663, ECO:0000269|PubMed:26874015,
CC ECO:0000269|PubMed:28446668, ECO:0000269|PubMed:30089697,
CC ECO:0000269|PubMed:31511391}.
CC -!- PTM: [Non-structural protein 5A]: Tyrosine phosphorylation is essential
CC for the interaction with host SRC. {ECO:0000269|PubMed:30862675}.
CC -!- PTM: [RNA-directed RNA polymerase]: The N-terminus is phosphorylated by
CC host PRK2/PKN2. {ECO:0000250|UniProtKB:P27958}.
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";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB047639; BAB32872.1; -; Genomic_RNA.
DR PDB; 2KZQ; NMR; -; A=684-719.
DR PDB; 2LIF; NMR; -; A=171-195.
DR PDB; 2LVG; NMR; -; A=1716-1755.
DR PDB; 2XXD; X-ray; 1.88 A; A=2443-3005.
DR PDB; 2XYM; X-ray; 1.77 A; A=2443-3005.
DR PDB; 3I5K; X-ray; 2.20 A; A/B/C/D=2443-3007.
DR PDB; 4AEP; X-ray; 1.80 A; A=2443-3013.
DR PDB; 4AEX; X-ray; 2.41 A; A/B=2443-3013.
DR PDB; 4E76; X-ray; 2.50 A; A=2443-2885, A=2896-3012.
DR PDB; 4E78; X-ray; 2.90 A; A=2443-2885, A=2896-3012.
DR PDB; 4E7A; X-ray; 3.00 A; A=2443-2885, A=2896-3012.
DR PDB; 4J1V; X-ray; 1.95 A; E/F/G/H=2284-2303.
DR PDB; 4OBC; X-ray; 2.50 A; A=2443-3012.
DR PDB; 4WT9; X-ray; 2.50 A; A=2443-2885, A=2896-3012.
DR PDB; 4WTA; X-ray; 2.80 A; A=2443-2885, A=2896-3012.
DR PDB; 4WTC; X-ray; 2.75 A; A=2443-2885, A=2896-3012.
DR PDB; 4WTD; X-ray; 2.70 A; A=2443-2885, A=2896-3012.
DR PDB; 4WTE; X-ray; 2.90 A; A=2443-2885, A=2896-3012.
DR PDB; 4WTF; X-ray; 2.65 A; A=2443-2885, A=2896-3012.
DR PDB; 4WTG; X-ray; 2.90 A; A=2443-2885, A=2896-3012.
DR PDB; 4WTI; X-ray; 2.80 A; A=2443-3012.
DR PDB; 4WTJ; X-ray; 2.20 A; A=2443-3012.
DR PDB; 4WTK; X-ray; 2.50 A; A=2443-3012.
DR PDB; 4WTL; X-ray; 2.00 A; A=2443-3012.
DR PDB; 4WTM; X-ray; 2.15 A; A=2443-3012.
DR PDB; 5NPJ; X-ray; 1.90 A; D/E=531-542.
DR PDB; 5QJ0; X-ray; 2.08 A; A=2443-3015.
DR PDB; 5QJ1; X-ray; 2.17 A; A=2443-3015.
DR PDB; 5TWM; X-ray; 1.97 A; A=2443-3015.
DR PDB; 5UJ2; X-ray; 2.90 A; A=2443-3012.
DR PDB; 6HT4; NMR; -; A=2280-2299.
DR PDBsum; 2KZQ; -.
DR PDBsum; 2LIF; -.
DR PDBsum; 2LVG; -.
DR PDBsum; 2XXD; -.
DR PDBsum; 2XYM; -.
DR PDBsum; 3I5K; -.
DR PDBsum; 4AEP; -.
DR PDBsum; 4AEX; -.
DR PDBsum; 4E76; -.
DR PDBsum; 4E78; -.
DR PDBsum; 4E7A; -.
DR PDBsum; 4J1V; -.
DR PDBsum; 4OBC; -.
DR PDBsum; 4WT9; -.
DR PDBsum; 4WTA; -.
DR PDBsum; 4WTC; -.
DR PDBsum; 4WTD; -.
DR PDBsum; 4WTE; -.
DR PDBsum; 4WTF; -.
DR PDBsum; 4WTG; -.
DR PDBsum; 4WTI; -.
DR PDBsum; 4WTJ; -.
DR PDBsum; 4WTK; -.
DR PDBsum; 4WTL; -.
DR PDBsum; 4WTM; -.
DR PDBsum; 5NPJ; -.
DR PDBsum; 5QJ0; -.
DR PDBsum; 5QJ1; -.
DR PDBsum; 5TWM; -.
DR PDBsum; 5UJ2; -.
DR PDBsum; 6HT4; -.
DR BMRB; Q99IB8; -.
DR SMR; Q99IB8; -.
DR DIP; DIP-48925N; -.
DR IntAct; Q99IB8; 345.
DR MINT; Q99IB8; -.
DR BindingDB; Q99IB8; -.
DR ChEMBL; CHEMBL4295932; -.
DR DrugCentral; Q99IB8; -.
DR MEROPS; S29.001; -.
DR ABCD; Q99IB8; 1 sequenced antibody.
DR euHCVdb; AB047639; -.
DR BRENDA; 3.4.21.98; 17000.
DR Reactome; R-HSA-5621480; Dectin-2 family.
DR EvolutionaryTrace; Q99IB8; -.
DR Proteomes; UP000008096; Genome.
DR GO; GO:0030430; C:host cell cytoplasm; IDA:AgBase.
DR GO; GO:0044165; C:host cell endoplasmic reticulum; IDA:AgBase.
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:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0044385; C:integral to membrane of host cell; IEA:UniProtKB-KW.
DR GO; GO:0019031; C:viral envelope; TAS:Reactome.
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:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005216; F:ion channel activity; IEA:UniProtKB-KW.
DR GO; GO:0003723; F:RNA binding; IMP:UniProtKB.
DR GO; GO:0003724; F:RNA helicase activity; IEA:UniProtKB-EC.
DR GO; GO:0003968; F:RNA-directed 5'-3' 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:0005160; F:transforming growth factor beta receptor binding; IPI:AgBase.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:AgBase.
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:0039654; P:fusion of virus membrane with host endosome membrane; IEA:UniProtKB-KW.
DR GO; GO:0052064; P:induction by symbiont of defense-related host reactive oxygen species production; IDA:AgBase.
DR GO; GO:0039520; P:induction by virus of host autophagy; IEA:UniProtKB-KW.
DR GO; GO:0039614; P:induction by virus of host protein phosphorylation; IDA:AgBase.
DR GO; GO:0039645; P:modulation by virus of host G1/S transition checkpoint; IEA:UniProtKB-KW.
DR GO; GO:1902902; P:negative regulation of autophagosome assembly; IDA:AgBase.
DR GO; GO:0010507; P:negative regulation of autophagy; IDA:AgBase.
DR GO; GO:1903147; P:negative regulation of autophagy of mitochondrion; IDA:AgBase.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:AgBase.
DR GO; GO:1903637; P:negative regulation of protein insertion into mitochondrial outer membrane; IDA:AgBase.
DR GO; GO:1903215; P:negative regulation of protein targeting to mitochondrion; IDA:AgBase.
DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:AgBase.
DR GO; GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; IDA:AgBase.
DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; IDA:AgBase.
DR GO; GO:0034156; P:negative regulation of toll-like receptor 7 signaling pathway; IDA:AgBase.
DR GO; GO:0034164; P:negative regulation of toll-like receptor 9 signaling pathway; IDA:AgBase.
DR GO; GO:0039707; P:pore formation by virus in membrane of host cell; IEA:UniProtKB-KW.
DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; IDA:AgBase.
DR GO; GO:0032914; P:positive regulation of transforming growth factor beta1 production; IDA:AgBase.
DR GO; GO:1901397; P:positive regulation of transforming growth factor beta2 activation; IDA:AgBase.
DR GO; GO:0051259; P:protein complex oligomerization; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0039563; P:suppression by virus of host JAK-STAT cascade via inhibition of STAT1 activity; IEA:UniProtKB-KW.
DR GO; GO:0039547; P:suppression by virus of host TRAF activity; IEA:UniProtKB-KW.
DR GO; GO:0039653; P:suppression by virus of host transcription; IDA:AgBase.
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 DisProt; DP01031; -.
DR Gene3D; 1.20.1280.150; -; 1.
DR Gene3D; 2.20.25.210; -; 1.
DR Gene3D; 2.20.25.220; -; 1.
DR Gene3D; 2.30.30.710; -; 1.
DR Gene3D; 2.40.10.10; -; 1.
DR Gene3D; 3.30.70.270; -; 2.
DR Gene3D; 3.40.50.300; -; 2.
DR Gene3D; 4.10.710.10; -; 1.
DR InterPro; IPR011492; DEAD_Flavivir.
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; NS3_Peptidase_S29.
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; SSF50494; SSF50494; 1.
DR SUPFAM; SSF52540; SSF52540; 2.
DR SUPFAM; SSF56672; SSF56672; 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..3033
FT /note="Genome polyprotein"
FT /id="PRO_0000450856"
FT CHAIN 2..191
FT /note="Core protein precursor"
FT /id="PRO_0000045592"
FT CHAIN 2..177
FT /note="Mature core protein"
FT /id="PRO_0000045593"
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_0000045594"
FT CHAIN 192..383
FT /note="Envelope glycoprotein E1"
FT /id="PRO_0000045595"
FT CHAIN 384..750
FT /note="Envelope glycoprotein E2"
FT /id="PRO_0000045596"
FT CHAIN 751..813
FT /note="Viroporin p7"
FT /id="PRO_0000045597"
FT CHAIN 814..1030
FT /note="Protease NS2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT /id="PRO_0000045598"
FT CHAIN 1031..1661
FT /note="Serine protease/helicase NS3"
FT /id="PRO_0000045599"
FT CHAIN 1662..1715
FT /note="Non-structural protein 4A"
FT /id="PRO_0000045600"
FT CHAIN 1716..1976
FT /note="Non-structural protein 4B"
FT /id="PRO_0000045601"
FT CHAIN 1977..2442
FT /note="Non-structural protein 5A"
FT /id="PRO_0000045602"
FT CHAIN 2443..3033
FT /note="RNA-directed RNA polymerase"
FT /id="PRO_0000045603"
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..729
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TRANSMEM 730..750
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TOPO_DOM 751..761
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:29253880"
FT TRANSMEM 762..782
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TOPO_DOM 783..785
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TRANSMEM 786..807
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TOPO_DOM 808..817
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TRANSMEM 818..838
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT TOPO_DOM 839..842
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT TRANSMEM 843..863
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT TOPO_DOM 864..885
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT TRANSMEM 886..906
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT TOPO_DOM 907..1661
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9WMX2"
FT TRANSMEM 1662..1682
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1683..1809
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 1810..1830
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1831..1832
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TRANSMEM 1833..1853
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1854
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 1855..1875
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1876..1885
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 1886..1906
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1907..1976
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT INTRAMEM 1977..2007
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TOPO_DOM 2008..3012
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT TRANSMEM 3013..3033
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DOMAIN 907..1030
FT /note="Peptidase C18"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT DOMAIN 1031..1212
FT /note="Peptidase S29"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT DOMAIN 1221..1373
FT /note="Helicase ATP-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT DOMAIN 2656..2774
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..411
FT /note="HVR1"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT REGION 484..496
FT /note="CD81-binding 1"
FT /evidence="ECO:0000250|UniProtKB:P26663"
FT REGION 524..555
FT /note="CD81-binding 2"
FT /evidence="ECO:0000250|UniProtKB:P26663"
FT REGION 664..675
FT /note="EIF2AK2/eIF2-alpha phosphorylation homology domain
FT (PePHD)"
FT REGION 908..1210
FT /note="Protease NS2-3"
FT /evidence="ECO:0000250|UniProtKB:P26663"
FT REGION 933..953
FT /note="Interaction with human SCPS1"
FT /evidence="ECO:0000269|PubMed:24009510"
FT REGION 1481..1501
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1490..1501
FT /note="RNA-binding"
FT /evidence="ECO:0000250|UniProtKB:P26663"
FT REGION 1683..1694
FT /note="NS3-binding"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT REGION 1837..1865
FT /note="Glycine zipper"
FT /evidence="ECO:0000269|PubMed:29167346"
FT REGION 1982..2002
FT /note="Membrane-binding"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT REGION 2009..2225
FT /note="D1; RNA-binding"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT REGION 2124..2332
FT /note="Transcriptional activation"
FT /evidence="ECO:0000255"
FT REGION 2124..2212
FT /note="FKBP8-binding"
FT /evidence="ECO:0000250|UniProtKB:P26662"
FT REGION 2139..2143
FT /note="Interaction with non-structural protein 4A"
FT /evidence="ECO:0000250|UniProtKB:P26662"
FT REGION 2192..2213
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2210..2249
FT /note="ISDR"
FT /evidence="ECO:0000250|UniProtKB:P26662"
FT REGION 2214..2275
FT /note="Interaction with EIF2AK2/PKR"
FT /evidence="ECO:0000250|UniProtKB:P26663"
FT REGION 2227..2315
FT /note="D2"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT REGION 2228..2315
FT /note="Disordered"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT REGION 2249..2306
FT /note="NS4B-binding"
FT /evidence="ECO:0000255"
FT REGION 2281..2297
FT /note="Interaction with human PPIA/CYPA"
FT /evidence="ECO:0000269|PubMed:21593166"
FT REGION 2329..2442
FT /note="D3"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT REGION 2336..2447
FT /note="Interaction with host IFI27"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT REGION 2352..2432
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2358..2381
FT /note="V3"
FT REGION 2371..2439
FT /note="Interaction with host VAPB"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT MOTIF 5..13
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:25485706"
FT MOTIF 38..43
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:25485706"
FT MOTIF 58..64
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:25485706"
FT MOTIF 66..71
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:25485706"
FT MOTIF 1320..1323
FT /note="DECH box"
FT /evidence="ECO:0000269|PubMed:30281972,
FT ECO:0000269|PubMed:31511391"
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..75
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2199..2213
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2352..2371
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 956
FT /note="For protease NS2 activity; shared with dimeric
FT partner"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT ACT_SITE 976
FT /note="For protease NS2 activity; shared with dimeric
FT partner"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT ACT_SITE 997
FT /note="For protease NS2 activity; shared with dimeric
FT partner"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT ACT_SITE 1087
FT /note="Charge relay system; for serine protease NS3
FT activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT ACT_SITE 1111
FT /note="Charge relay system; for serine protease NS3
FT activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT ACT_SITE 1169
FT /note="Charge relay system; for serine protease NS3
FT activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT BINDING 1127
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="structural"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT BINDING 1129
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="structural"
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"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT BINDING 1179
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="structural"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
FT BINDING 1234..1241
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT BINDING 1241
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 1321
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:0000305|PubMed:30281972"
FT BINDING 2015
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 2033
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 2035
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 2056
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 2662
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 2760
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 2761
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 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 750..751
FT /note="Cleavage; by host signal peptidase"
FT /evidence="ECO:0000250"
FT SITE 813..814
FT /note="Cleavage; by host signal peptidase"
FT /evidence="ECO:0000250"
FT SITE 1030..1031
FT /note="Cleavage; by protease NS2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
FT SITE 1661..1662
FT /note="Cleavage; by serine protease/helicase NS3"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT SITE 1715..1716
FT /note="Cleavage; by serine protease/helicase NS3"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT SITE 1976..1977
FT /note="Cleavage; by serine protease/helicase NS3"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT SITE 2442..2443
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 2069
FT /note="Phosphotyrosine; by host"
FT /evidence="ECO:0000269|PubMed:30862675"
FT MOD_RES 2198
FT /note="Phosphoserine; by host; in p56"
FT /evidence="ECO:0000269|PubMed:26874015,
FT ECO:0000269|PubMed:28446668"
FT MOD_RES 2201
FT /note="Phosphoserine; by host; in p58"
FT /evidence="ECO:0000250|UniProtKB:P26662"
FT MOD_RES 2205
FT /note="Phosphoserine; by host; in p56 and p58, regulates
FT intracellular NS5A distribution"
FT /evidence="ECO:0000269|PubMed:30089697,
FT ECO:0000269|PubMed:31511391"
FT MOD_RES 2208
FT /note="Phosphoserine; by host; in p58"
FT /evidence="ECO:0000269|PubMed:28446668,
FT ECO:0000269|PubMed:30089697, ECO:0000269|PubMed:31511391"
FT MOD_RES 2211
FT /note="Phosphoserine; by host; in p58"
FT /evidence="ECO:0000269|PubMed:26874015,
FT ECO:0000269|PubMed:28446668, ECO:0000269|PubMed:30089697,
FT ECO:0000269|PubMed:31511391"
FT MOD_RES 2214
FT /note="Phosphoserine; by host; in p58"
FT /evidence="ECO:0000269|PubMed:31511391"
FT MOD_RES 2324
FT /note="Phosphothreonine; by host"
FT /evidence="ECO:0000269|PubMed:26874015"
FT LIPID 926
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 LIPID 1976
FT /note="S-palmitoyl cysteine; by host; partial"
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...) (high mannose) asparagine; by
FT host"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT CARBOHYD 477
FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT host"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT CARBOHYD 534
FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT host"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT CARBOHYD 542
FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT host"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT CARBOHYD 558
FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT host"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT CARBOHYD 578
FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT host"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT CARBOHYD 627
FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT host"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT CARBOHYD 649
FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by
FT host"
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 429..554
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 452..459
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 488..496
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 505..510
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 566..571
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 585..589
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 601..624
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 611..648
FT /evidence="ECO:0000250|UniProtKB:P27958"
FT DISULFID 656..681
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 1322
FT /note="C->A: Cleaves ATP 50% slower and unwinds DNA 18%
FT more slowly."
FT /evidence="ECO:0000269|PubMed:30281972"
FT MUTAGEN 1322
FT /note="C->G: No effect on NS3 helicase activity; 50%
FT decreased in nucleic acid binding; decreases the affinity
FT of NS3 helicase for Mg2+ by 2 orders of magnitude."
FT /evidence="ECO:0000269|PubMed:30281972"
FT MUTAGEN 2011
FT /note="P->A: Slight reduction in infectivity."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2019
FT /note="Y->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2021
FT /note="G->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2023
FT /note="W->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2027
FT /note="G->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2035
FT /note="C->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2036
FT /note="G->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2043
FT /note="V->A: Complete loss of virus production. Disrupts
FT the dimerization and localization of NS5A to lipid
FT droplets. NS5A binding to HCV 3'UTR RNA."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2072
FT /note="G->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2110
FT /note="T->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2121
FT /note="P->A: Complete loss of virus production. Disrupts
FT the dimerization and localization of NS5A to lipid
FT droplets. Increased affinity of NS5A binding to HCV 3'UTR
FT RNA."
FT /evidence="ECO:0000269|PubMed:29352312"
FT MUTAGEN 2205
FT /note="S->A: Complete loss of phosphorylation at S-2205, S-
FT 2208 and S-2211."
FT /evidence="ECO:0000269|PubMed:28446668"
FT MUTAGEN 2208
FT /note="S->A: Complete loss of phosphorylation at S-2208 and
FT S-2211."
FT /evidence="ECO:0000269|PubMed:28446668"
FT MUTAGEN 2211
FT /note="S->A: Complete loss of phosphorylation of S-2211.
FT Increases phosphorylation of S-2205. Complete loss of
FT infectivity."
FT /evidence="ECO:0000269|PubMed:26874015,
FT ECO:0000269|PubMed:31511391"
FT MUTAGEN 2211
FT /note="S->D: Alters virus-induced membrane rearrangements,
FT no effect on virus infectivity."
FT /evidence="ECO:0000269|PubMed:26874015"
FT MUTAGEN 2292
FT /note="D->E: No loss of its RNA-binding ability or
FT interaction with human PPIA/CYPA but loss of PPIA/CYPA-
FT mediated stimulation of its RNA-binding ability; alone or
FT when associated with N-2293."
FT /evidence="ECO:0000269|PubMed:21593166"
FT MUTAGEN 2293
FT /note="Y->N: No loss of its RNA-binding ability or
FT interaction with human PPIA/CYPA but loss of PPIA/CYPA-
FT mediated stimulation of its RNA-binding ability; when
FT associated with E-2292."
FT /evidence="ECO:0000269|PubMed:21593166"
FT MUTAGEN 2324
FT /note="T->A,D: No effect on viral replication and virus
FT production."
FT /evidence="ECO:0000269|PubMed:26874015"
FT MUTAGEN 2428..2433
FT /note="SWSTCS->AWATCA: Complete loss of interaction with
FT mature core protein."
FT /evidence="ECO:0000269|PubMed:18524832"
FT MUTAGEN 2428..2430
FT /note="SWS->EWE: No effect on the interaction with mature
FT core protein."
FT /evidence="ECO:0000269|PubMed:18524832"
FT HELIX 175..185
FT /evidence="ECO:0007829|PDB:2LIF"
FT HELIX 189..194
FT /evidence="ECO:0007829|PDB:2LIF"
FT HELIX 537..541
FT /evidence="ECO:0007829|PDB:5NPJ"
FT HELIX 692..701
FT /evidence="ECO:0007829|PDB:2KZQ"
FT TURN 702..706
FT /evidence="ECO:0007829|PDB:2KZQ"
FT HELIX 710..714
FT /evidence="ECO:0007829|PDB:2KZQ"
FT TURN 715..718
FT /evidence="ECO:0007829|PDB:2KZQ"
FT HELIX 1719..1748
FT /evidence="ECO:0007829|PDB:2LVG"
FT STRAND 2444..2448
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2467..2470
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2476..2478
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2479..2481
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2484..2486
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2487..2494
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2504..2517
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2527..2532
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2542..2544
FT /evidence="ECO:0007829|PDB:5TWM"
FT HELIX 2547..2552
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2557..2570
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2572..2574
FT /evidence="ECO:0007829|PDB:2XXD"
FT STRAND 2578..2582
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2586..2588
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2591..2593
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2601..2604
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2607..2629
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2630..2632
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2634..2636
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2639..2651
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2653..2663
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2666..2669
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2672..2684
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2689..2701
FT /evidence="ECO:0007829|PDB:2XYM"
FT TURN 2702..2704
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2706..2709
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2715..2719
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2729..2748
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2754..2758
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2761..2767
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2771..2787
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2792..2794
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2799..2801
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2802..2804
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2810..2816
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2818..2820
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2822..2828
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2831..2842
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2846..2849
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2850..2856
FT /evidence="ECO:0007829|PDB:2XYM"
FT TURN 2857..2859
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2861..2865
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2867..2878
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2881..2883
FT /evidence="ECO:0007829|PDB:4E76"
FT STRAND 2885..2889
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2892..2896
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2898..2900
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2901..2909
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2911..2914
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2921..2934
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2939..2955
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2958..2967
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2969..2971
FT /evidence="ECO:0007829|PDB:2XYM"
FT STRAND 2972..2974
FT /evidence="ECO:0007829|PDB:4WTL"
FT HELIX 2982..2986
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2992..2996
FT /evidence="ECO:0007829|PDB:2XYM"
FT HELIX 2998..3000
FT /evidence="ECO:0007829|PDB:4AEP"
FT STRAND 3002..3004
FT /evidence="ECO:0007829|PDB:5TWM"
SQ SEQUENCE 3033 AA; 328828 MW; 7E5BEA79702AF95B CRC64;
MSTNPKPQRK TKRNTNRRPE DVKFPGGGQI VGGVYLLPRR GPRLGVRTTR KTSERSQPRG
RRQPIPKDRR STGKAWGKPG RPWPLYGNEG LGWAGWLLSP RGSRPSWGPT DPRHRSRNVG
KVIDTLTCGF ADLMGYIPVV GAPLSGAARA VAHGVRVLED GVNYATGNLP GFPFSIFLLA
LLSCITVPVS AAQVKNTSSS YMVTNDCSND SITWQLEAAV LHVPGCVPCE RVGNTSRCWV
PVSPNMAVRQ PGALTQGLRT HIDMVVMSAT FCSALYVGDL CGGVMLAAQV FIVSPQYHWF
VQECNCSIYP GTITGHRMAW DMMMNWSPTA TMILAYVMRV PEVIIDIVSG AHWGVMFGLA
YFSMQGAWAK VIVILLLAAG VDAGTTTVGG AVARSTNVIA GVFSHGPQQN IQLINTNGSW
HINRTALNCN DSLNTGFLAA LFYTNRFNSS GCPGRLSACR NIEAFRIGWG TLQYEDNVTN
PEDMRPYCWH YPPKPCGVVP ARSVCGPVYC FTPSPVVVGT TDRRGVPTYT WGENETDVFL
LNSTRPPQGS WFGCTWMNST GFTKTCGAPP CRTRADFNAS TDLLCPTDCF RKHPDATYIK
CGSGPWLTPK CLVHYPYRLW HYPCTVNFTI FKIRMYVGGV EHRLTAACNF TRGDRCDLED
RDRSQLSPLL HSTTEWAILP CTYSDLPALS TGLLHLHQNI VDVQYMYGLS PAITKYVVRW
EWVVLLFLLL ADARVCACLW MLILLGQAEA ALEKLVVLHA ASAANCHGLL YFAIFFVAAW
HIRGRVVPLT TYCLTGLWPF CLLLMALPRQ AYAYDAPVHG QIGVGLLILI TLFTLTPGYK
TLLGQCLWWL CYLLTLGEAM IQEWVPPMQV RGGRDGIAWA VTIFCPGVVF DITKWLLALL
GPAYLLRAAL THVPYFVRAH ALIRVCALVK QLAGGRYVQV ALLALGRWTG TYIYDHLTPM
SDWAASGLRD LAVAVEPIIF SPMEKKVIVW GAETAACGDI LHGLPVSARL GQEILLGPAD
GYTSKGWKLL APITAYAQQT RGLLGAIVVS MTGRDRTEQA GEVQILSTVS QSFLGTTISG
VLWTVYHGAG NKTLAGLRGP VTQMYSSAEG DLVGWPSPPG TKSLEPCKCG AVDLYLVTRN
ADVIPARRRG DKRGALLSPR PISTLKGSSG GPVLCPRGHV VGLFRAAVCS RGVAKSIDFI
PVETLDVVTR SPTFSDNSTP PAVPQTYQVG YLHAPTGSGK STKVPVAYAA QGYKVLVLNP
SVAATLGFGA YLSKAHGINP NIRTGVRTVM TGEAITYSTY GKFLADGGCA SGAYDIIICD
ECHAVDATSI LGIGTVLDQA ETAGVRLTVL ATATPPGSVT TPHPDIEEVG LGREGEIPFY
GRAIPLSCIK GGRHLIFCHS KKKCDELAAA LRGMGLNAVA YYRGLDVSII PAQGDVVVVA
TDALMTGYTG DFDSVIDCNV AVTQAVDFSL DPTFTITTQT VPQDAVSRSQ RRGRTGRGRQ
GTYRYVSTGE RASGMFDSVV LCECYDAGAA WYDLTPAETT VRLRAYFNTP GLPVCQDHLE
FWEAVFTGLT HIDAHFLSQT KQAGENFAYL VAYQATVCAR AKAPPPSWDA MWKCLARLKP
TLAGPTPLLY RLGPITNEVT LTHPGTKYIA TCMQADLEVM TSTWVLAGGV LAAVAAYCLA
TGCVSIIGRL HVNQRVVVAP DKEVLYEAFD EMEECASRAA LIEEGQRIAE MLKSKIQGLL
QQASKQAQDI QPAMQASWPK VEQFWARHMW NFISGIQYLA GLSTLPGNPA VASMMAFSAA
LTSPLSTSTT ILLNIMGGWL ASQIAPPAGA TGFVVSGLVG AAVGSIGLGK VLVDILAGYG
AGISGALVAF KIMSGEKPSM EDVINLLPGI LSPGALVVGV ICAAILRRHV GPGEGAVQWM
NRLIAFASRG NHVAPTHYVT ESDASQRVTQ LLGSLTITSL LRRLHNWITE DCPIPCSGSW
LRDVWDWVCT ILTDFKNWLT SKLFPKLPGL PFISCQKGYK GVWAGTGIMT TRCPCGANIS
GNVRLGSMRI TGPKTCMNTW QGTFPINCYT EGQCAPKPPT NYKTAIWRVA ASEYAEVTQH
GSYSYVTGLT TDNLKIPCQL PSPEFFSWVD GVQIHRFAPT PKPFFRDEVS FCVGLNSYAV
GSQLPCEPEP DADVLRSMLT DPPHITAETA ARRLARGSPP SEASSSVSQL SAPSLRATCT
THSNTYDVDM VDANLLMEGG VAQTEPESRV PVLDFLEPMA EEESDLEPSI PSECMLPRSG
FPRALPAWAR PDYNPPLVES WRRPDYQPPT VAGCALPPPK KAPTPPPRRR RTVGLSESTI
SEALQQLAIK TFGQPPSSGD AGSSTGAGAA ESGGPTSPGE PAPSETGSAS SMPPLEGEPG
DPDLESDQVE LQPPPQGGGV APGSGSGSWS TCSEEDDTTV CCSMSYSWTG ALITPCSPEE
EKLPINPLSN SLLRYHNKVY CTTSKSASQR AKKVTFDRTQ VLDAHYDSVL KDIKLAASKV
SARLLTLEEA CQLTPPHSAR SKYGFGAKEV RSLSGRAVNH IKSVWKDLLE DPQTPIPTTI
MAKNEVFCVD PAKGGKKPAR LIVYPDLGVR VCEKMALYDI TQKLPQAVMG ASYGFQYSPA
QRVEYLLKAW AEKKDPMGFS YDTRCFDSTV TERDIRTEES IYQACSLPEE ARTAIHSLTE
RLYVGGPMFN SKGQTCGYRR CRASGVLTTS MGNTITCYVK ALAACKAAGI VAPTMLVCGD
DLVVISESQG TEEDERNLRA FTEAMTRYSA PPGDPPRPEY DLELITSCSS NVSVALGPRG
RRRYYLTRDP TTPLARAAWE TVRHSPINSW LGNIIQYAPT IWVRMVLMTH FFSILMVQDT
LDQNLNFEMY GSVYSVNPLD LPAIIERLHG LDAFSMHTYS HHELTRVASA LRKLGAPPLR
VWKSRARAVR ASLISRGGKA AVCGRYLFNW AVKTKLKLTP LPEARLLDLS SWFTVGAGGG
DIFHSVSRAR PRSLLFGLLL LFVGVGLFLL PAR
