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 04-NOV-2026, entry version 192. 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; Hepaciviridae; Orthohepacivirus; Orthohepacivirus hominis. 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:21347350, CC PubMed:31121874). {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. Initiates RNA transcription/replication at a flavin CC adenine dinucleotide (FAD), resulting in a 5'- FAD cap on viral RNAs. CC In this way, recognition of viral 5' RNA by host pattern recognition CC receptors can be bypassed, thereby evading activation of antiviral CC pathways. {ECO:0000250|UniProtKB:P27958}. CC -!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]: CC Reaction=Hydrolysis of four peptide bonds in the viral precursor CC polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr CC in P1 and Ser or Ala in P1'.; EC=3.4.21.98; CC Evidence={ECO:0000250|UniProtKB:P27958}; CC -!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]: CC Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'- CC diphosphate + phosphate + H(+); 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 + phosphate + H(+); 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=RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + CC diphosphate; 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 Interacts with host NEURL3; this interaction prevents E1 binding to CC glycoprotein E2 (By similarity). {ECO:0000250|UniProtKB:P27958, CC ECO:0000269|PubMed:21347350, ECO:0000269|PubMed:24009510, CC 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). Interacts with host TRIM14; this CC interaction induces the degradation of NS5A (By similarity). CC {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P26663, CC ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958, CC ECO:0000269|PubMed:18524832, ECO:0000269|PubMed:21593166, CC ECO:0000269|PubMed:24223774, ECO:0000269|PubMed:28566381, CC ECO:0000269|PubMed:28912275, ECO:0000269|PubMed:29352312, CC ECO:0000269|PubMed:30862675, ECO:0000269|PubMed:31121874, CC 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_0000045596; PRO_0000045595 [Q99IB8]: -; NbExp=5; IntAct=EBI-6901449, EBI-6901441; 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_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_0000045597 [Q99IB8]: -; NbExp=4; IntAct=EBI-6901421, EBI-8772829; 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 a 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:21593166, CC PubMed:28912275, PubMed:31315928). 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:26874015, PubMed:28446668). p58 is a CC hyperphosphorylated form of p56 (PubMed:26874015, PubMed:28446668, CC PubMed:30089697, PubMed:31511391). 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 --------------------------------------------------------------------------- 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 PDB; 9LJR; X-ray; 2.74 A; A=2443-2995. DR PDB; 9LJS; X-ray; 2.96 A; A=2443-2995. DR PDB; 9LJT; X-ray; 3.46 A; A=2443-2995. DR PDB; 9LJU; X-ray; 2.92 A; A=2443-2995. DR PDB; 9LJV; X-ray; 2.25 A; A=2443-2995. DR PDB; 9LJW; X-ray; 3.13 A; A=2443-2993. DR BMRB; Q99IB8; -. DR SMR; Q99IB8; -. DR DIP; DIP-48925N; -. DR IntAct; Q99IB8; 345. DR BindingDB; Q99IB8; -. DR ChEMBL; CHEMBL4295932; -. DR DrugCentral; Q99IB8; -. DR MEROPS; S29.001; -. DR GlyCosmos; Q99IB8; 15 sites, No reported glycans. DR iPTMnet; Q99IB8; -. DR ABCD; Q99IB8; 1 sequenced antibody. DR euHCVdb; AB047639; -. DR BRENDA; 3.4.21.98; 17000. DR BRENDA; 5.6.2.6; 17000. DR Reactome; R-HSA-5621480; Dectin-2 family. DR EvolutionaryTrace; Q99IB8; -. DR GO; GO:0030430; C:host cell cytoplasm; EXP:UniProtKB. DR GO; GO:0044167; C:host cell endoplasmic reticulum membrane; EXP:UniProtKB. DR GO; GO:0044186; C:host cell lipid droplet; EXP:UniProtKB. DR GO; GO:0044191; C:host cell mitochondrial membrane; ISS:UniProtKB. DR GO; GO:0033650; C:host cell mitochondrion; ISS:UniProtKB. DR GO; GO:0042025; C:host cell nucleus; ISS:UniProtKB. DR GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0020002; C:host cell plasma membrane; EXP:UniProtKB. DR GO; GO:1990904; C:ribonucleoprotein complex; 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; EXP:UniProtKB. DR GO; GO:0015267; F:channel activity; IEA:UniProtKB-KW. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0017111; F:ribonucleoside triphosphate phosphatase activity; EXP:UniProtKB. 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 RNA polymerase activity; IEA:UniProtKB-KW. DR GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro. DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW. DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0075512; P:clathrin-dependent endocytosis of virus by host cell; IEA:UniProtKB-KW. DR GO; GO:0039654; P:fusion of virus membrane with host endosome membrane; IEA:UniProtKB-KW. DR GO; GO:0034220; P:monoatomic ion transmembrane transport; IEA:UniProtKB-KW. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR GO; GO:0039520; P:symbiont-mediated activation of host autophagy; IEA:UniProtKB-KW. DR GO; GO:0039645; P:symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint; IEA:UniProtKB-KW. DR GO; GO:0039545; P:symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity; IEA:UniProtKB-KW. DR GO; GO:0140476; P:symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TRAF activity; IEA:UniProtKB-KW. DR GO; GO:0039563; P:symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity; IEA:UniProtKB-KW. DR GO; GO:0039502; P:symbiont-mediated suppression of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW. DR GO; GO:0019087; P:symbiont-mediated transformation of host cell; 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 CDD; cd20903; HCV_p7; 1. DR CDD; cd23202; Hepacivirus_RdRp; 1. DR DisProt; DP01031; -. DR FunFam; 2.30.30.710:FF:000001; Genome polyprotein; 1. DR FunFam; 3.30.160.890:FF:000001; Genome polyprotein; 1. DR FunFam; 3.30.70.270:FF:000015; Genome polyprotein; 1. DR FunFam; 3.40.50.300:FF:000557; Genome polyprotein; 1. DR FunFam; 3.40.50.300:FF:000717; Genome polyprotein; 1. DR FunFam; 4.10.710.10:FF:000001; Genome polyprotein; 1. DR Gene3D; 2.40.10.120; -; 1. DR Gene3D; 3.30.70.270; -; 2. DR Gene3D; 6.10.250.1610; -; 1. DR Gene3D; 6.10.250.1750; -; 1. DR Gene3D; 6.10.250.2920; -; 1. DR Gene3D; 2.20.25.210; Hepatitis C NS5A, domain 1B; 1. DR Gene3D; 4.10.710.10; Hepatitis C Virus Capsid Protein, Chain A; 1. DR Gene3D; 3.30.160.890; Hepatitis C virus envelope glycoprotein E1, chain C; 1. DR Gene3D; 2.30.30.710; Hepatitis C virus non-structural protein NS2, C-terminal domain; 1. DR Gene3D; 1.20.1280.150; Hepatitis C virus non-structural protein NS2, N-terminal domain; 1. DR Gene3D; 2.20.25.220; Hepatitis C virus NS5A, 1B domain; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR Gene3D; 1.10.820.10; RNA Helicase Chain A , domain 3; 1. DR Gene3D; 2.40.10.10; Trypsin-like serine proteases; 1. DR InterPro; IPR043502; DNA/RNA_pol_sf. DR InterPro; IPR011492; Flavi_DEAD. DR InterPro; IPR002521; HCV_Core_C. DR InterPro; IPR044896; HCV_core_chain_A. DR InterPro; IPR002522; HCV_core_N. DR InterPro; IPR002519; HCV_Env. DR InterPro; IPR002531; HCV_NS1. DR InterPro; IPR002518; HCV_NS2. DR InterPro; IPR042205; HCV_NS2_C. DR InterPro; IPR042209; HCV_NS2_N. DR InterPro; IPR000745; HCV_NS4a. DR InterPro; IPR001490; HCV_NS4b. DR InterPro; IPR002868; HCV_NS5a. DR InterPro; IPR013192; HCV_NS5A_1a. DR InterPro; IPR013193; HCV_NS5a_1B_dom. DR InterPro; IPR038568; HCV_NS5A_1B_sf. DR InterPro; IPR024350; HCV_NS5a_C. DR InterPro; IPR049913; HCV_p7. DR InterPro; IPR014001; Helicase_ATP-bd. DR InterPro; IPR001650; Helicase_C-like. DR InterPro; IPR004109; HepC_NS3_protease. DR InterPro; IPR054175; NS3_helicase_C. DR InterPro; IPR038170; NS5A_1a_sf. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR009003; Peptidase_S1_PA. 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; PF22027; NS3_helicase_C; 1. DR Pfam; PF02907; Peptidase_S29; 1. DR Pfam; PF00998; RdRP_3; 1. DR SMART; SM00487; DEXDc; 1. DR SUPFAM; SSF56672; DNA/RNA polymerases; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 2. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS51693; HCV_NS2_PRO; 1. DR PROSITE; PS51192; HELICASE_ATP_BIND_1; 1. DR PROSITE; PS51194; HELICASE_CTER; 1. DR PROSITE; PS51822; HV_PV_NS3_PRO; 1. DR PROSITE; PS50507; RDRP_SSRNA_POS; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Activation of host autophagy by virus; KW Apoptosis; ATP-binding; Capsid protein; KW Clathrin-mediated endocytosis of virus by host; Disulfide bond; KW Fusion of virus membrane with host endosomal membrane; KW Fusion of virus membrane with host membrane; KW G1/S host cell cycle checkpoint dysregulation by virus; Glycoprotein; KW Helicase; Host cell membrane; Host cytoplasm; Host endoplasmic reticulum; KW Host lipid droplet; Host membrane; Host mitochondrion; Host nucleus; KW Host-virus interaction; Hydrolase; KW Inhibition of host innate immune response by virus; KW Inhibition of host interferon signaling pathway by virus; KW Inhibition of host MAVS by virus; Inhibition of host RLR pathway by virus; KW Inhibition of host STAT1 by virus; Inhibition of host TRAFs by virus; KW Interferon antiviral system evasion; Ion channel; Ion transport; KW Isopeptide bond; Lipoprotein; Magnesium; Membrane; Metal-binding; KW Modulation of host cell cycle by virus; Multifunctional enzyme; KW Nucleotide-binding; Nucleotidyltransferase; Oncogene; Palmitate; KW Phosphoprotein; Protease; Ribonucleoprotein; RNA-binding; KW RNA-directed RNA polymerase; Serine protease; SH3-binding; Thiol protease; KW Transcription; Transcription regulation; Transferase; Transmembrane; KW Transmembrane helix; Transport; Ubl conjugation; KW Viral attachment to host cell; Viral envelope protein; Viral immunoevasion; KW Viral ion channel; Viral nucleoprotein; KW Viral penetration into host cytoplasm; Viral RNA replication; Virion; KW Virus endocytosis by host; Virus entry into host cell; Zinc. FT INIT_MET 1 FT /note="Removed; by host" FT /evidence="ECO:0000250|UniProtKB:P26664" FT CHAIN 2..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 7..16 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 32..47 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2196..2213 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2316..2326 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2355..2379 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2398..2408 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2417..2426 FT /note="Gly 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'UTRRNA." 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 FT 3'UTRRNA." FT /evidence="ECO:0000269|PubMed:29352312" FT MUTAGEN 2205 FT /note="S->A: Complete loss of phosphorylation at S-2205, FT S-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 FT PPIA/CYPA-mediated stimulation of its RNA-binding ability; FT alone or 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 FT PPIA/CYPA-mediated stimulation of its RNA-binding ability; FT when 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 2458..2462 FT /evidence="ECO:0007829|PDB:4WTL" 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 2523..2526 FT /evidence="ECO:0007829|PDB:4WT9" FT HELIX 2527..2532 FT /evidence="ECO:0007829|PDB:2XYM" FT HELIX 2538..2541 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 HELIX 2597..2600 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..2698 FT /evidence="ECO:0007829|PDB:2XYM" FT HELIX 2699..2703 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 STRAND 2724..2726 FT /evidence="ECO:0007829|PDB:9LJW" 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 2863..2867 FT /evidence="ECO:0007829|PDB:2XYM" FT HELIX 2868..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 2975..2981 FT /evidence="ECO:0007829|PDB:2XYM" FT HELIX 2982..2986 FT /evidence="ECO:0007829|PDB:2XYM" FT STRAND 2992..2994 FT /evidence="ECO:0007829|PDB:4AEP" FT HELIX 2998..3000 FT /evidence="ECO:0007829|PDB:2XYM" 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 //