ID POLG_HCVJA Reviewed; 3010 AA. AC P26662; P89966; Q81755; DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 3. DT 27-MAR-2024, entry version 215. 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:0000269|PubMed:9060645}; DE EC=3.6.1.15 {ECO:0000269|PubMed:20398661}; DE EC=3.6.4.13 {ECO:0000269|PubMed:20398661}; DE AltName: Full=Hepacivirin; DE AltName: Full=NS3 helicase {ECO:0000250|UniProtKB:P27958}; DE AltName: Full=NS3 protease {ECO:0000250|UniProtKB:P27958}; DE AltName: Full=NS3P; DE AltName: Full=Viroporin p70; DE Contains: DE RecName: Full=Non-structural protein 4A; DE Short=NS4A; DE AltName: Full=p8; DE Contains: DE RecName: Full=Non-structural protein 4B; DE Short=NS4B; DE AltName: Full=p27; DE Contains: DE RecName: Full=Non-structural protein 5A; DE Short=NS5A; DE AltName: Full=p56/58; DE Contains: DE RecName: Full=RNA-directed RNA polymerase; DE EC=2.7.7.48 {ECO:0000269|PubMed:11907226}; DE AltName: Full=NS5B; DE AltName: Full=p68; OS Hepatitis C virus genotype 1b (isolate Japanese) (HCV). OC Viruses; Riboviria; Orthornavirae; Kitrinoviricota; Flasuviricetes; OC Amarillovirales; Flaviviridae; Hepacivirus; Hepacivirus hominis. OX NCBI_TaxID=11116; OH NCBI_TaxID=9606; Homo sapiens (Human). RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA]. RX PubMed=2175903; DOI=10.1073/pnas.87.24.9524; RA Kato N., Hijikata M., Ootsuyama Y., Nakagawa M., Ohkoshi S., Sugimura T., RA Shimotohno K.; RT "Molecular cloning of the human hepatitis C virus genome from Japanese RT patients with non-A, non-B hepatitis."; RL Proc. Natl. Acad. Sci. U.S.A. 87:9524-9528(1990). RN [2] RP DISCUSSION OF SEQUENCE. RX PubMed=1849488; DOI=10.1016/0014-5793(91)80322-t; RA Kato N., Hijikata M., Nakagawa M., Ootsuyama Y., Muraiso K., Ohkoshi S., RA Shimotohno K.; RT "Molecular structure of the Japanese hepatitis C viral genome."; RL FEBS Lett. 280:325-328(1991). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA]. RA Tanaka T.; RL Submitted (JAN-1997) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 723-1908, IDENTIFICATION (PROTEASE RP NS2), MUTAGENESIS OF CYS-922; HIS-932; HIS-952; GLU-972; GLU-980; CYS-993; RP GLU-1009; GLU-1058; HIS-1083; ASP-1107; CYS-1123; CYS-1125; HIS-1136; RP SER-1165; CYS-1171; HIS-1175; CYS-1185; GLU-1199; GLU-1202; HIS-1227 AND RP HIS-1229, IDENTIFICATION (SERINE PROTEASE/HELICASE NS3), AND ACTIVE SITE RP (SERINE PROTEASE/HELICASE NS3). RX PubMed=8392606; DOI=10.1128/jvi.67.8.4665-4675.1993; RA Hijikata M., Mizushima H., Akagi T., Mori S., Kakiuchi N., Kato N., RA Tanaka T., Kimura K., Shimotohno K.; RT "Two distinct proteinase activities required for the processing of a RT putative nonstructural precursor protein of hepatitis C virus."; RL J. Virol. 67:4665-4675(1993). RN [5] RP PROTEOLYTIC CLEAVAGE (GENOME POLYPROTEIN). RX PubMed=1648221; DOI=10.1073/pnas.88.13.5547; RA Hijikata M., Kato N., Ootsuyama Y., Nakagawa M., Shimotohno K.; RT "Gene mapping of the putative structural region of the hepatitis C virus RT genome by in vitro processing analysis."; RL Proc. Natl. Acad. Sci. U.S.A. 88:5547-5551(1991). RN [6] RP INHIBITION OF HEPATITIS B VIRUS GENE EXPRESSION. RX PubMed=8396658; DOI=10.1128/jvi.67.10.5823-5832.1993; RA Shih C.-M., Lo S.J., Miyamura T., Chen S.-Y., Lee Y.-H.W.; RT "Suppression of hepatitis B virus expression and replication by hepatitis C RT virus core protein in HuH-7 cells."; RL J. Virol. 67:5823-5832(1993). RN [7] RP PROTEOLYTIC PROCESSING (GENOME POLYPROTEIN), MUTAGENESIS OF HIS-1083; RP ASP-1107 AND SER-1165, IDENTIFICATION (SERINE PROTEASE/HELICASE NS3), AND RP ACTIVE SITE (SERINE PROTEASE/HELICASE NS3). RX PubMed=8389908; DOI=10.1128/jvi.67.7.3835-3844.1993; RA Bartenschlager R., Ahlborn-Laake L., Mous J., Jacobsen H.; RT "Nonstructural protein 3 of the hepatitis C virus encodes a serine-type RT proteinase required for cleavage at the NS3/4 and NS4/5 junctions."; RL J. Virol. 67:3835-3844(1993). RN [8] RP PHOSPHORYLATION (NON-STRUCTURAL PROTEIN 5A). RX PubMed=7999043; DOI=10.1006/bbrc.1994.2667; RA Kaneko T., Tanji Y., Satoh S., Hijikata M., Asabe S., Kimura K., RA Shimotohno K.; RT "Production of two phosphoproteins from the NS5A region of the hepatitis C RT viral genome."; RL Biochem. Biophys. Res. Commun. 205:320-326(1994). RN [9] RP MUTAGENESIS OF SER-2194; SER-2197; SER-2200; SER-2201; SER-2202; SER-2204; RP SER-2207; SER-2210 AND SER-2221, PHOSPHORYLATION AT SER-2194; SER-2197; RP SER-2201 AND SER-2204, PHOSPHORYLATION (NON-STRUCTURAL PROTEIN 5A), AND RP SUBCELLULAR LOCATION (NON-STRUCTURAL PROTEIN 5A). RX PubMed=7769656; DOI=10.1128/jvi.69.7.3980-3986.1995; RA Tanji Y., Kaneko T., Satoh S., Shimotohno K.; RT "Phosphorylation of hepatitis C virus-encoded nonstructural protein NS5A."; RL J. Virol. 69:3980-3986(1995). RN [10] RP INTERACTION WITH NON-STRUCTURAL PROTEIN 4A (NON-STRUCTURAL PROTEIN 5A), AND RP INTERACTION WITH NON-STRUCTURAL PROTEIN 5A (NON-STRUCTURAL PROTEIN 4A). RX PubMed=8985418; DOI=10.1128/jvi.71.1.790-796.1997; RA Asabe S.I., Tanji Y., Satoh S., Kaneko T., Kimura K., Shimotohno K.; RT "The N-terminal region of hepatitis C virus-encoded NS5A is important for RT NS4A-dependent phosphorylation."; RL J. Virol. 71:790-796(1997). RN [11] RP FUNCTION (NON-STRUCTURAL PROTEIN 5A). RX PubMed=9343247; DOI=10.1128/jvi.71.11.8856-8859.1997; RA Kato N., Lan K.H., Ono-Nita S.K., Shiratori Y., Omata M.; RT "Hepatitis C virus nonstructural region 5A protein is a potent RT transcriptional activator."; RL J. Virol. 71:8856-8859(1997). RN [12] RP ZINC-BINDING (SERINE PROTEASE/HELICASE NS3), COFACTOR (SERINE RP PROTEASE/HELICASE NS3), MUTAGENESIS OF CYS-1042; CYS-1073; CYS-1078; RP HIS-1083; HIS-1136; SER-1165; HIS-1175; CYS-1185; HIS-1227 AND HIS-1229, RP ACTIVE SITE (SERINE PROTEASE/HELICASE NS3), DOMAIN (SERINE RP PROTEASE/HELICASE NS3), AND CATALYTIC ACTIVITY (SERINE PROTEASE/HELICASE RP NS3). RX PubMed=9060645; DOI=10.1128/jvi.71.4.2881-2886.1997; RA Stempniak M., Hostomska Z., Nodes B.R., Hostomsky Z.; RT "The NS3 proteinase domain of hepatitis C virus is a zinc-containing RT enzyme."; RL J. Virol. 71:2881-2886(1997). RN [13] RP SUBCELLULAR LOCATION (MATURE CORE PROTEIN), AND PROTEOLYTIC CLEAVAGE RP (GENOME POLYPROTEIN). RX PubMed=9621068; DOI=10.1128/jvi.72.7.6048-6055.1998; RA Yasui K., Wakita T., Tsukiyama-Kohara K., Funahashi S., Ichikawa M., RA Kajita T., Moradpour D., Wands J.R., Kohara M.; RT "The native form and maturation process of hepatitis C virus core RT protein."; RL J. Virol. 72:6048-6055(1998). RN [14] RP DOMAIN (NON-STRUCTURAL PROTEIN 5A). RX PubMed=9525599; DOI=10.1128/jvi.72.4.2795-2805.1998; RA Pawlotsky J.-M., Germanidis G., Neumann A.U., Pellerin M., Frainais P.-O., RA Dhumeaux D.; RT "Interferon resistance of hepatitis C virus genotype 1b: relationship to RT nonstructural 5A gene quasispecies mutations."; RL J. Virol. 72:2795-2805(1998). RN [15] RP SUBCELLULAR LOCATION (NON-STRUCTURAL PROTEIN 5A), NUCLEAR LOCALIZATION RP REGION (NON-STRUCTURAL PROTEIN 5A), AND PROTEOLYTIC CLEAVAGE RP (NON-STRUCTURAL PROTEIN 5A). RX PubMed=10793006; DOI=10.1006/viro.2000.0287; RA Satoh S., Hirota M., Noguchi T., Hijikata M., Handa H., Shimotohno K.; RT "Cleavage of hepatitis C virus nonstructural protein 5A by a caspase-like RT protease(s) in mammalian cells."; RL Virology 270:476-487(2000). RN [16] RP REVIEW. RX PubMed=10718937; DOI=10.1046/j.1365-2893.2000.00201.x; RA McLauchlan J.; RT "Properties of the hepatitis C virus core protein: a structural protein RT that modulates cellular processes."; RL J. Viral Hepat. 7:2-14(2000). RN [17] RP OLIGOMERIZATION (RNA-DIRECTED RNA POLYMERASE), AND CATALYTIC ACTIVITY RP (RNA-DIRECTED RNA POLYMERASE). RX PubMed=11907226; DOI=10.1128/jvi.76.8.3865-3872.2002; RA Wang Q.M., Hockman M.A., Staschke K., Johnson R.B., Case K.A., Lu J., RA Parsons S., Zhang F., Rathnachalam R., Kirkegaard K., Colacino J.M.; RT "Oligomerization and cooperative RNA synthesis activity of hepatitis C RT virus RNA-dependent RNA polymerase."; RL J. Virol. 76:3865-3872(2002). RN [18] RP INTERACTION WITH HOST SP110 (MATURE CORE PROTEIN), AND FUNCTION (MATURE RP CORE PROTEIN). RX PubMed=14559998; DOI=10.1128/mcb.23.21.7498-7509.2003; RA Watashi K., Hijikata M., Tagawa A., Doi T., Marusawa H., Shimotohno K.; RT "Modulation of retinoid signaling by a cytoplasmic viral protein via RT sequestration of Sp110b, a potent transcriptional corepressor of retinoic RT acid receptor, from the nucleus."; RL Mol. Cell. Biol. 23:7498-7509(2003). RN [19] RP MUTAGENESIS OF LEU-139; VAL-140; LEU-144; 176-ILE-PHE-177; 178-LEU-LEU-179; RP 181-LEU-LEU-182 AND 183-SER-CYS-184, PROTEOLYTIC CLEAVAGE (GENOME RP POLYPROTEIN), SUBCELLULAR LOCATION (MATURE CORE PROTEIN), AND SUBCELLULAR RP LOCATION (CORE PROTEIN PRECURSOR). RX PubMed=15163730; DOI=10.1128/jvi.78.12.6370-6380.2004; RA Okamoto K., Moriishi K., Miyamura T., Matsuura Y.; RT "Intramembrane proteolysis and endoplasmic reticulum retention of hepatitis RT C virus core protein."; RL J. Virol. 78:6370-6380(2004). RN [20] 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 [21] RP FUNCTION (MATURE CORE PROTEIN). RX PubMed=15760888; DOI=10.1074/jbc.m501826200; RA Boni S., Lavergne J.-P., Boulant S., Cahour A.; RT "Hepatitis C virus core protein acts as a trans-modulating factor on RT internal translation initiation of the viral RNA."; RL J. Biol. Chem. 280:17737-17748(2005). RN [22] RP INTERACTION WITH HOST STAT1 (MATURE CORE PROTEIN), AND FUNCTION (MATURE RP CORE PROTEIN). RX PubMed=15825084; DOI=10.1053/j.gastro.2005.02.006; RA Lin W., Choe W.H., Hiasa Y., Kamegaya Y., Blackard J.T., Schmidt E.V., RA Chung R.T.; RT "Hepatitis C virus expression suppresses interferon signaling by degrading RT STAT1."; RL Gastroenterology 128:1034-1041(2005). RN [23] RP SUBCELLULAR LOCATION (MATURE CORE PROTEIN). RX PubMed=15613354; DOI=10.1128/jvi.79.2.1271-1281.2005; RA Suzuki R., Sakamoto S., Tsutsumi T., Rikimaru A., Tanaka K., Shimoike T., RA Moriishi K., Iwasaki T., Mizumoto K., Matsuura Y., Miyamura T., Suzuki T.; RT "Molecular determinants for subcellular localization of hepatitis C virus RT core protein."; RL J. Virol. 79:1271-1281(2005). RN [24] RP FUNCTION (NON-STRUCTURAL PROTEIN 5A), AND RNA-BINDING (NON-STRUCTURAL RP PROTEIN 5A). RX PubMed=16126720; DOI=10.1074/jbc.m508175200; RA Huang L., Hwang J., Sharma S.D., Hargittai M.R., Chen Y., Arnold J.J., RA Raney K.D., Cameron C.E.; RT "Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding RT protein."; RL J. Biol. Chem. 280:36417-36428(2005). RN [25] RP INTERACTION WITH HOST VAPB (NON-STRUCTURAL PROTEIN 5A), INTERACTION WITH RP HOST VAPB (RNA-DIRECTED RNA POLYMERASE), AND SUBCELLULAR LOCATION RP (NON-STRUCTURAL PROTEIN 5A). RX PubMed=16227268; DOI=10.1128/jvi.79.21.13473-13482.2005; RA Hamamoto I., Nishimura Y., Okamoto T., Aizaki H., Liu M., Mori Y., Abe T., RA Suzuki T., Lai M.M., Miyamura T., Moriishi K., Matsuura Y.; RT "Human VAP-B is involved in hepatitis C virus replication through RT interaction with NS5A and NS5B."; RL J. Virol. 79:13473-13482(2005). RN [26] RP PROTEOLYTIC CLEAVAGE (NON-STRUCTURAL PROTEIN 5A). RX PubMed=16517592; DOI=10.1074/jbc.m601124200; RA Kalamvoki M., Georgopoulou U., Mavromara P.; RT "The NS5A protein of the hepatitis C virus genotype 1a is cleaved by RT caspases to produce C-terminal-truncated forms of the protein that reside RT mainly in the cytosol."; RL J. Biol. Chem. 281:13449-13462(2006). RN [27] RP INTERACTION WITH HOST STAT1 (MATURE CORE PROTEIN), AND FUNCTION (MATURE RP CORE PROTEIN). RX PubMed=16940534; DOI=10.1128/jvi.00459-06; RA Lin W., Kim S.S., Yeung E., Kamegaya Y., Blackard J.T., Kim K.A., RA Holtzman M.J., Chung R.T.; RT "Hepatitis C virus core protein blocks interferon signaling by interaction RT with the STAT1 SH2 domain."; RL J. Virol. 80:9226-9235(2006). RN [28] RP INTERACTION WITH HOST FKBP8 (NON-STRUCTURAL PROTEIN 5A), AND SUBCELLULAR RP LOCATION (NON-STRUCTURAL PROTEIN 5A). RX PubMed=16844119; DOI=10.1016/j.febslet.2006.07.002; RA Wang J., Tong W., Zhang X., Chen L., Yi Z., Pan T., Hu Y., Xiang L., RA Yuan Z.; RT "Hepatitis C virus non-structural protein NS5A interacts with FKBP38 and RT inhibits apoptosis in Huh7 hepatoma cells."; RL FEBS Lett. 580:4392-4400(2006). RN [29] RP INTERACTION WITH HOST EIF2AK2 (MATURE CORE PROTEIN). RX PubMed=17267064; DOI=10.1016/j.virusres.2006.12.010; RA Yan X.B., Battaglia S., Boucreux D., Chen Z., Brechot C., Pavio N.; RT "Mapping of the interacting domains of hepatitis C virus core protein and RT the double-stranded RNA-activated protein kinase PKR."; RL Virus Res. 125:79-87(2007). RN [30] RP INTERACTION WITH HOST EIF2AK2 (NON-STRUCTURAL PROTEIN 5A), AND DOMAIN RP (NON-STRUCTURAL PROTEIN 5A). RX PubMed=17451199; DOI=10.3748/wjg.v13.i8.1195; RA Veillon P., Payan C., Le Guillou-Guillemette H., Gaudy C., Lunel F.; RT "Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b RT during interferon or combined interferon-ribavirin therapy."; RL World J. Gastroenterol. 13:1195-1203(2007). RN [31] RP FUNCTION (SERINE PROTEASE/HELICASE NS3), CATALYTIC ACTIVITY (SERINE RP PROTEASE/HELICASE NS3), AND COFACTOR (SERINE PROTEASE/HELICASE NS3). RX PubMed=20398661; DOI=10.1016/j.febslet.2010.04.020; RA Huang Z.S., Wang C.C., Wu H.N.; RT "HCV NS3 protein helicase domain assists RNA structure conversion."; RL FEBS Lett. 584:2356-2362(2010). RN [32] RP GLYCOSYLATION AT THR-385; THR-396; SER-401; SER-404; THR-473 AND THR-518, RP AND IDENTIFICATION BY MASS SPECTROMETRY. RC STRAIN=HCV-S; RX PubMed=23242014; DOI=10.1093/glycob/cws171; RA Braeutigam J., Scheidig A.J., Egge-Jacobsen W.; RT "Mass spectrometric analysis of hepatitis C viral envelope protein E2 RT reveals extended microheterogeneity of mucin-type O-linked glycosylation."; RL Glycobiology 23:453-474(2013). RN [33] RP INTERACTION WITH HOST RAB18 (NON-STRUCTURAL PROTEIN 5A), AND SUBCELLULAR RP LOCATION (NON-STRUCTURAL PROTEIN 5A). RX PubMed=23935497; DOI=10.1371/journal.ppat.1003513; RA Salloum S., Wang H., Ferguson C., Parton R.G., Tai A.W.; RT "Rab18 binds to hepatitis C virus NS5A and promotes interaction between RT sites of viral replication and lipid droplets."; RL PLoS Pathog. 9:e1003513-e1003513(2013). RN [34] RP FUNCTION (NON-STRUCTURAL PROTEIN 5A), SUBCELLULAR LOCATION (NON-STRUCTURAL RP PROTEIN 5A), DOMAIN (NON-STRUCTURAL PROTEIN 5A), NUCLEAR LOCALIZATION RP REGION (NON-STRUCTURAL PROTEIN 5A), AND MUTAGENESIS OF ASP-2126. RX PubMed=23468497; DOI=10.1128/jvi.00585-12; RA Maqbool M.A., Imache M.R., Higgs M.R., Carmouse S., Pawlotsky J.M., RA Lerat H.; RT "Regulation of hepatitis C virus replication by nuclear translocation of RT nonstructural 5A protein and transcriptional activation of host genes."; RL J. Virol. 87:5523-5539(2013). RN [35] RP PHOSPHORYLATION AT SER-2448 AND SER-2461, PHOSPHORYLATION (RNA-DIRECTED RNA RP POLYMERASE), AND MUTAGENESIS OF SER-2448 AND SER-2461. RX PubMed=25031343; DOI=10.1128/jvi.01826-14; RA Han S.H., Kim S.J., Kim E.J., Kim T.E., Moon J.S., Kim G.W., Lee S.H., RA Cho K., Yoo J.S., Son W.S., Rhee J.K., Han S.H., Oh J.W.; RT "Phosphorylation of hepatitis C virus RNA polymerases ser29 and ser42 by RT protein kinase C-related kinase 2 regulates viral RNA replication."; RL J. Virol. 88:11240-11252(2014). RN [36] RP FUNCTION (NON-STRUCTURAL PROTEIN 5A), MUTAGENESIS OF SER-2194; SER-2197; RP SER-2201; SER-2204; SER-2207 AND SER-2210, AND SUBUNIT (NON-STRUCTURAL RP PROTEIN 5A). RX PubMed=31585734; DOI=10.1016/j.bbrc.2019.09.105; RA Kandangwa M., Liu Q.; RT "HCV NS5A hyperphosphorylation is involved in viral translation RT modulation."; RL Biochem. Biophys. Res. Commun. 520:192-197(2019). RN [37] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1027-1213. RX PubMed=10702283; DOI=10.1074/jbc.275.10.7152; RA Di Marco S., Rizzi M., Volpari C., Walsh M.A., Narjes F., Colarusso S., RA De Francesco R., Matassa V.G., Sollazzo M.; RT "Inhibition of the hepatitis C virus NS3/4A protease. The crystal RT structures of two protease-inhibitor complexes."; RL J. Biol. Chem. 275:7152-7157(2000). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1027-1213 IN COMPLEX WITH A RP PEPTIDOMIMETIC INHIBITOR. RX PubMed=15588076; DOI=10.1021/jm049435d; RA Ontoria J.M., Di Marco S., Conte I., Di Francesco M.E., Gardelli C., RA Koch U., Matassa V.G., Poma M., Steinkuehler C., Volpari C., Harper S.; RT "The design and enzyme-bound crystal structure of indoline based RT peptidomimetic inhibitors of hepatitis C virus NS3 protease."; RL J. Med. Chem. 47:6443-6446(2004). RN [39] {ECO:0007744|PDB:2K8J} RP STRUCTURE BY NMR OF 781-809, AND FUNCTION (VIROPORIN P7). RX PubMed=20667830; DOI=10.1074/jbc.m110.122895; RA Montserret R., Saint N., Vanbelle C., Salvay A.G., Simorre J.P., Ebel C., RA Sapay N., Renisio J.G., Bockmann A., Steinmann E., Pietschmann T., RA Dubuisson J., Chipot C., Penin F.; RT "NMR structure and ion channel activity of the p7 protein from hepatitis C RT virus."; RL J. Biol. Chem. 285:31446-31461(2010). RN [40] {ECO:0007744|PDB:3P8N, ECO:0007744|PDB:3P8O} RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1027-1206 AND 1678-1691. RX PubMed=21270126; DOI=10.1074/jbc.m110.211417; RA Lemke C.T., Goudreau N., Zhao S., Hucke O., Thibeault D., Llinas-Brunet M., RA White P.W.; RT "Combined X-ray, NMR, and kinetic analyses reveal uncommon binding RT characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI RT 201335."; RL J. Biol. Chem. 286:11434-11443(2011). RN [41] {ECO:0007744|PDB:3OYP} RP X-RAY CRYSTALLOGRAPHY (2.76 ANGSTROMS) OF 1027-1213 AND 1678-1691 IN RP COMPLEX WITH ZINC. RX PubMed=21113170; DOI=10.1038/nchembio.492; RA Hagel M., Niu D., St Martin T., Sheets M.P., Qiao L., Bernard H., RA Karp R.M., Zhu Z., Labenski M.T., Chaturvedi P., Nacht M., Westlin W.F., RA Petter R.C., Singh J.; RT "Selective irreversible inhibition of a protease by targeting a RT noncatalytic cysteine."; RL Nat. Chem. Biol. 7:22-24(2011). RN [42] {ECO:0007744|PDB:4A1T, ECO:0007744|PDB:4A1V, ECO:0007744|PDB:4A1X} RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1028-1206 AND 1678-1690 IN RP COMPLEX WITH ZINC. RX PubMed=22965230; DOI=10.1074/jbc.m112.393843; RA Kugler J., Schmelz S., Gentzsch J., Haid S., Pollmann E., RA van den Heuvel J., Franke R., Pietschmann T., Heinz D.W., Collins J.; RT "High affinity peptide inhibitors of the hepatitis C virus NS3-4A protease RT refractory to common resistant mutants."; RL J. Biol. Chem. 287:39224-39232(2012). RN [43] {ECO:0007744|PDB:4I31, ECO:0007744|PDB:4I32, ECO:0007744|PDB:4I33} RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1027-1206; 1208-1208 AND RP 1678-1691. RX PubMed=23271737; DOI=10.1074/jbc.m112.439455; RA O'Meara J.A., Lemke C.T., Godbout C., Kukolj G., Lagace L., Moreau B., RA Thibeault D., White P.W., Llinas-Brunet M.; RT "Molecular mechanism by which a potent hepatitis C virus NS3-NS4A protease RT inhibitor overcomes emergence of resistance."; RL J. Biol. Chem. 288:5673-5681(2013). RN [44] {ECO:0007744|PDB:4JMY} RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 1678-1691. RA LaPlante S., Lemke C.T.; RT "Importance of the peptide scaffold of drugs that target the hepatitis C RT virus NS3 protease and its crucial bioactive conformation and dynamic RT factors."; RL Submitted (MAR-2013) to the PDB data bank. RN [45] {ECO:0007744|PDB:4KTC} RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1028-1213 IN COMPLEX WITH ZINC. RX PubMed=23672640; DOI=10.1021/jm400164c; RA Jiang Y., Andrews S.W., Condroski K.R., Buckman B., Serebryany V., RA Wenglowsky S., Kennedy A.L., Madduru M.R., Wang B., Lyon M., Doherty G.A., RA Woodard B.T., Lemieux C., Geck Do M., Zhang H., Ballard J., Vigers G., RA Brandhuber B.J., Stengel P., Josey J.A., Beigelman L., Blatt L., RA Seiwert S.D.; RT "Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent RT inhibitor of hepatitis C virus (HCV) NS3/4A protease."; RL J. Med. Chem. 57:1753-1769(2014). CC -!- FUNCTION: [Mature core protein]: Packages viral RNA to form a viral CC nucleocapsid, and promotes virion budding (Probable). Participates in CC the viral particle production as a result of its interaction with the CC non-structural protein 5A (By similarity). Binds RNA and may function CC as a RNA chaperone to induce the RNA structural rearrangements taking CC place during virus replication (By similarity). Modulates viral CC translation initiation by interacting with viral IRES and 40S ribosomal CC subunit (PubMed:15760888). Affects various cell signaling pathways, CC host immunity and lipid metabolism (Probable). Prevents the CC establishment of cellular antiviral state by blocking the interferon- CC alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by CC blocking the formation of phosphorylated STAT1 and promoting ubiquitin- CC mediated proteasome-dependent degradation of STAT1 (PubMed:16940534, CC PubMed:15825084). Activates STAT3 leading to cellular transformation CC (By similarity). Regulates the activity of cellular genes, including c- CC myc and c-fos (By similarity). May repress the promoter of p53, and CC sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm CC (PubMed:14559998). Represses cell cycle negative regulating factor CC CDKN1A, thereby interrupting an important check point of normal cell CC cycle regulation (By similarity). Targets transcription factors CC involved in the regulation of inflammatory responses and in the immune CC response: suppresses NF-kappa-B activation, and activates AP-1 (By CC similarity). Binds to dendritic cells (DCs) via C1QR1, resulting in CC down-regulation of T-lymphocytes proliferation (By similarity). Alters CC lipid metabolism by interacting with hepatocellular proteins involved CC in lipid accumulation and storage (By similarity). Induces up- CC regulation of FAS promoter activity, and thereby contributes to the CC increased triglyceride accumulation in hepatocytes (steatosis) (By CC similarity). {ECO:0000250|UniProtKB:P26664, CC ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:P29846, CC ECO:0000250|UniProtKB:Q99IB8, ECO:0000269|PubMed:14559998, CC ECO:0000269|PubMed:15760888, ECO:0000269|PubMed:15825084, CC ECO:0000269|PubMed:16940534, ECO:0000305}. CC -!- FUNCTION: [Envelope glycoprotein E1]: Forms a heterodimer with envelope CC glycoprotein E2, which mediates virus attachment to the host cell, CC virion internalization through clathrin-dependent endocytosis and CC fusion with host membrane (By similarity). Fusion with the host cell is CC most likely mediated by both E1 and E2, through conformational CC rearrangements of the heterodimer required for fusion rather than a CC classical class II fusion mechanism (By similarity). E1/E2 heterodimer CC binds host apolipoproteins such as APOB and APOE thereby forming a CC lipo-viro-particle (LVP) (By similarity). APOE associated to the LVP CC allows the initial virus attachment to cell surface receptors such as CC the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan- CC 1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger CC receptor class B type I (SCARB1) (By similarity). The cholesterol CC transfer activity of SCARB1 allows E2 exposure and binding of E2 to CC SCARB1 and the tetraspanin CD81 (By similarity). E1/E2 heterodimer CC binding on CD81 activates the epithelial growth factor receptor (EGFR) CC signaling pathway (By similarity). Diffusion of the complex E1-E2-EGFR- CC SCARB1-CD81 to the cell lateral membrane allows further interaction CC with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry CC (By similarity). {ECO:0000250|UniProtKB:P27958}. CC -!- FUNCTION: [Envelope glycoprotein E2]: Forms a heterodimer with envelope CC glycoprotein E1, which mediates virus attachment to the host cell, CC virion internalization through clathrin-dependent endocytosis and CC fusion with host membrane (By similarity). Fusion with the host cell is CC most likely mediated by both E1 and E2, through conformational CC rearrangements of the heterodimer required for fusion rather than a CC classical class II fusion mechanism (By similarity). The interaction CC between envelope glycoprotein E2 and host apolipoprotein E/APOE allows CC the proper assembly, maturation and infectivity of the viral particles CC (By similarity). This interaction is probably promoted via the up- CC regulation of cellular autophagy by the virus (By similarity). E1/E2 CC heterodimer binds host apolipoproteins such as APOB and APOE thereby CC forming a lipo-viro-particle (LVP) (By similarity). APOE associated to CC the LVP allows the initial virus attachment to cell surface receptors CC such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), CC syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and CC scavenger receptor class B type I (SCARB1) (By similarity). The CC cholesterol transfer activity of SCARB1 allows E2 exposure and binding CC of E2 to SCARB1 and the tetraspanin CD81 (By similarity). E1/E2 CC heterodimer binding on CD81 activates the epithelial growth factor CC receptor (EGFR) signaling pathway (By similarity). Diffusion of the CC complex E1-E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows CC further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to CC finally trigger HCV entry (By similarity). Inhibits host EIF2AK2/PKR CC activation, preventing the establishment of an antiviral state (By CC similarity). Viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which CC are respectively found on dendritic cells (DCs), and on liver CC sinusoidal endothelial cells and macrophage-like cells of lymph node CC sinuses (By similarity). These interactions allow the capture of CC circulating HCV particles by these cells and subsequent facilitated CC transmission to permissive cells such as hepatocytes and lymphocyte CC subpopulations (By similarity). The interaction between E2 and host CC amino acid transporter complex formed by SLC3A2 and SLC7A5/LAT1 may CC facilitate viral entry into host cell (By similarity). CC {ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958}. CC -!- FUNCTION: [Viroporin p7]: Ion channel protein that acts as a viroporin CC and plays an essential role in the assembly, envelopment and secretion CC of viral particles (PubMed:20667830). Regulates the host cell secretory CC pathway, which induces the intracellular retention of viral CC glycoproteins and favors assembly of viral particles (By similarity). CC Creates a pore in acidic organelles and releases Ca(2+) and H(+) in the CC cytoplasm of infected cells, leading to a productive viral infection CC (By similarity). High levels of cytoplasmic Ca(2+) may trigger membrane CC trafficking and transport of viral ER-associated proteins to CC viroplasms, sites of viral genome replication (Probable). This ionic CC imbalance induces the assembly of the inflammasome complex, which CC triggers the maturation of pro-IL-1beta into IL-1beta through the CC action of caspase-1 (By similarity). Targets also host mitochondria and CC induces mitochondrial depolarization (By similarity). In addition of CC its role as a viroporin, acts as a lipid raft adhesion factor (By CC similarity). {ECO:0000250|UniProtKB:P27958, CC ECO:0000250|UniProtKB:Q99IB8, ECO:0000269|PubMed:20667830, CC ECO:0000305}. CC -!- FUNCTION: [Protease NS2]: Cysteine protease required for the CC proteolytic auto-cleavage between the non-structural proteins NS2 and CC NS3 (By similarity). The N-terminus of NS3 is required for the function CC of NS2 protease (active region NS2-3) (By similarity). Promotes the CC initiation of viral particle assembly by mediating the interaction CC between structural and non-structural proteins (By similarity). CC {ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P27958, CC ECO:0000250|UniProtKB:Q99IB8}. CC -!- FUNCTION: [Serine protease/helicase NS3]: Displays three enzymatic CC activities: serine protease with a chymotrypsin-like fold, NTPase and CC RNA helicase (By similarity). NS3 serine protease, in association with CC NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B- CC NS5A and NS5A-NS5B (By similarity). The NS3/NS4A complex prevents CC phosphorylation of host IRF3, thus preventing the establishment of CC dsRNA induced antiviral state (By similarity). The NS3/NS4A complex CC induces host amino acid transporter component SLC3A2, thus contributing CC to HCV propagation (By similarity). NS3 RNA helicase binds to RNA and CC unwinds both dsDNA and dsRNA in the 3' to 5' direction, and likely CC resolves RNA complicated stable secondary structures in the template CC strand (By similarity). Binds a single ATP and catalyzes the unzipping CC of a single base pair of dsRNA (By similarity). Inhibits host antiviral CC proteins TBK1 and IRF3 thereby preventing the establishment of an CC antiviral state (By similarity). Cleaves host MAVS/CARDIF thereby CC preventing the establishment of an antiviral state (By similarity). CC Cleaves host TICAM1/TRIF, thereby disrupting TLR3 signaling and CC preventing the establishment of an antiviral state (By similarity). CC {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q9WMX2}. CC -!- FUNCTION: [Non-structural protein 4A]: Peptide cofactor which forms a CC non-covalent complex with the N-terminal of NS3 serine protease (By CC similarity). The NS3/NS4A complex prevents phosphorylation of host CC IRF3, thus preventing the establishment of dsRNA induced antiviral CC state (By similarity). The NS3/NS4A complex induces host amino acid CC transporter component SLC3A2, thus contributing to HCV propagation (By CC similarity). {ECO:0000250|UniProtKB:P27958, CC ECO:0000250|UniProtKB:Q9WMX2}. CC -!- FUNCTION: [Non-structural protein 4B]: Induces a specific membrane CC alteration that serves as a scaffold for the virus replication complex CC (By similarity). This membrane alteration gives rise to the so-called CC ER-derived membranous web that contains the replication complex (By CC similarity). NS4B self-interaction contributes to its function in CC membranous web formation (By similarity). Promotes host TRIF protein CC degradation in a CASP8-dependent manner thereby inhibiting host TLR3- CC mediated interferon signaling (By similarity). Disrupts the interaction CC between STING and TBK1 contributing to the inhibition of interferon CC signaling (By similarity). {ECO:0000250|UniProtKB:P27958}. CC -!- FUNCTION: [Non-structural protein 5A]: Phosphorylated protein that is CC indispensable for viral replication and assembly (By similarity). Both CC hypo- and hyperphosphorylated states are required for the viral life CC cycle (By similarity). The hyperphosphorylated form of NS5A is an CC inhibitor of viral replication (By similarity). Involved in RNA-binding CC and especially in binding to the viral genome (PubMed:16126720). Zinc CC is essential for RNA-binding (By similarity). Participates in the viral CC particle production as a result of its interaction with the mature CC viral core protein (By similarity). Its interaction with host VAPB may CC target the viral replication complex to vesicles (Probable). Down- CC regulates viral IRES translation initiation (PubMed:31585734). Mediates CC interferon resistance, presumably by interacting with and inhibiting CC host EIF2AK2/PKR (By similarity). Prevents BIN1-induced apoptosis (By CC similarity). Acts as a transcriptional activator of some host genes CC important for viral replication when localized in the nucleus CC (PubMed:23468497) (Probable). Via the interaction with host PACSIN2, CC modulates lipid droplet formation in order to promote virion assembly CC (By similarity). Modulates TNFRSF21/DR6 signaling pathway for viral CC propagation (By similarity). {ECO:0000250|UniProtKB:P27958, CC ECO:0000250|UniProtKB:Q99IB8, ECO:0000250|UniProtKB:Q9WMX2, CC ECO:0000269|PubMed:16126720, ECO:0000269|PubMed:23468497, CC ECO:0000269|PubMed:31585734, ECO:0000305|PubMed:16227268, CC ECO:0000305|PubMed:9343247}. 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:0000269|PubMed:9060645}; CC -!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]: CC Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'- CC diphosphate + H(+) + phosphate; Xref=Rhea:RHEA:23680, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:57930, ChEBI:CHEBI:61557; EC=3.6.1.15; CC Evidence={ECO:0000269|PubMed:20398661}; CC -!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]: CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13; CC Evidence={ECO:0000269|PubMed:20398661}; CC -!- CATALYTIC ACTIVITY: [RNA-directed RNA polymerase]: CC Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate + CC RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA- CC COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395; CC EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539, CC ECO:0000269|PubMed:11907226}; 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:0000269|PubMed:9060645}; CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:Q9WMX2}; CC Note=Binds 1 zinc ion, which has a structural role (PubMed:9060645). CC The magnesium ion is essential for the helicase activity CC (PubMed:20398661). {ECO:0000269|PubMed:20398661, CC ECO:0000269|PubMed:9060645}; 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 (Probable). Inhibition by amantadine appears to be genotype- CC dependent (Probable). Also inhibited by long-alkyl-chain iminosugar CC derivatives (By similarity). {ECO:0000250|UniProtKB:P27958, CC ECO:0000305|PubMed:20667830}. CC -!- ACTIVITY REGULATION: [RNA-directed RNA polymerase]: Activity is up- CC regulated by PRK2/PKN2-mediated phosphorylation. CC {ECO:0000250|UniProtKB:P27958}. CC -!- SUBUNIT: [Mature core protein]: Homooligomer (By similarity). Interacts CC with E1 (via C-terminus) (By similarity). Interacts with the non- CC structural protein 5A (By similarity). Interacts (via N-terminus) with CC host STAT1 (via SH2 domain); this interaction results in decreased CC STAT1 phosphorylation and ubiquitin-mediated proteasome-dependent STAT1 CC degradation, leading to decreased IFN-stimulated gene transcription CC (PubMed:16940534, PubMed:15825084). Interacts with host STAT3; this CC interaction constitutively activates STAT3 (By similarity). Interacts CC with host LTBR receptor (By similarity). Interacts with host TNFRSF1A CC receptor and possibly induces apoptosis (By similarity). Interacts with CC host HNRPK (By similarity). Interacts with host YWHAE (By similarity). CC Interacts with host UBE3A/E6AP (By similarity). Interacts with host CC DDX3X (By similarity). Interacts with host APOA2 (By similarity). CC Interacts with host RXRA protein (By similarity). Interacts with host CC SP110 isoform 3/Sp110b; this interaction sequesters the transcriptional CC corepressor SP110 away from the nucleus (PubMed:14559998). Interacts CC with host CREB3 nuclear transcription protein; this interaction CC triggers cell transformation (By similarity). Interacts with host ACY3 CC (By similarity). Interacts with host C1QR1 (By similarity). Interacts CC with host RBM24; this interaction, which enhances the interaction of CC the mature core protein with 5'-UTR, may inhibit viral translation and CC favor replication (By similarity). Interacts with host EIF2AK2/PKR; CC this interaction induces the autophosphorylation of EIF2AK2 CC (PubMed:17267064). Part of the viral assembly initiation complex CC composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein CC (By similarity). {ECO:0000250|UniProtKB:P27958, CC ECO:0000250|UniProtKB:P29846, ECO:0000250|UniProtKB:Q03463, CC ECO:0000250|UniProtKB:Q5EG65, ECO:0000250|UniProtKB:Q99IB8, CC ECO:0000269|PubMed:14559998, ECO:0000269|PubMed:15825084, CC ECO:0000269|PubMed:16940534, ECO:0000269|PubMed:17267064}. CC -!- SUBUNIT: [Envelope glycoprotein E1]: Forms a heterodimer with envelope CC glycoprotein E2 (By similarity). Interacts with mature core protein (By CC similarity). Interacts with protease NS2 (By similarity). The CC heterodimer E1/E2 interacts with host CLDN1; this interaction plays a CC role in viral entry into host cell (By similarity). Interacts with host CC SPSB2 (via C-terminus) (By similarity). Part of the viral assembly CC initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the CC mature core protein (By similarity). Interacts with host NEURL3; this CC interaction prevents E1 binding to glycoprotein E2 (By similarity). CC {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8}. CC -!- SUBUNIT: [Envelope glycoprotein E2]: Forms a heterodimer with envelope CC glycoprotein E1 (By similarity). Interacts with host CD81 and SCARB1 CC receptors; these interactions play a role in viral entry into host cell CC (By similarity). Interacts with host EIF2AK2/PKR; this interaction CC inhibits EIF2AK2 and probably allows the virus to evade the innate CC immune response (By similarity). Interacts with host CD209/DC-SIGN and CC CLEC4M/DC-SIGNR (By similarity). Interact with host SPCS1; this CC interaction is essential for viral particle assembly (By similarity). CC Interacts with protease NS2 (By similarity). The heterodimer E1/E2 CC interacts with host CLDN1; this interaction plays a role in viral entry CC into host cell (By similarity). Part of the viral assembly initiation CC complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core CC protein (By similarity). Interacts with host SLC3A2/4F2hc; the CC interaction may facilitate viral entry into host cell (By similarity). CC Interacts with human PLSCR1 (By similarity). CC {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8, CC ECO:0000250|UniProtKB:Q9WMX2}. CC -!- SUBUNIT: [Viroporin p7]: Homohexamer (By similarity). Homoheptamer (By CC similarity). Interacts with protease NS2 (By similarity). CC {ECO:0000250|UniProtKB:O92972, ECO:0000250|UniProtKB:P27958, CC ECO:0000250|UniProtKB:Q99IB8}. CC -!- SUBUNIT: [Protease NS2]: Homodimer (By similarity). Interacts with host CC SPCS1; this interaction is essential for viral particle assembly (By CC similarity). Interacts with envelope glycoprotein E1 (By similarity). CC Interacts with envelope glycoprotein E2 (By similarity). Interacts with CC viroporin p7 (By similarity). Interacts with serine protease/helicase CC NS3 (By similarity). Part of the replication complex composed of NS2, CC NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in CC an ER-derived membranous web (By similarity). Part of the viral CC assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A CC and the mature core protein (By similarity). CC {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8}. CC -!- SUBUNIT: [Serine protease/helicase NS3]: Interacts with protease NS2 CC (By similarity). Interacts with non-structural protein 4A; this CC interaction stabilizes the folding of NS3 serine protease (By CC similarity). NS3-NS4A interaction is essential for NS3 activation and CC allows membrane anchorage of the latter (By similarity). NS3/NS4A CC complex also prevents phosphorylation of host IRF3, thus preventing the CC establishment of dsRNA induced antiviral state (By similarity). CC Interacts with host MAVS; this interaction leads to the cleavage and CC inhibition of host MAVS (By similarity). Interacts with host TICAM1; CC this interaction leads to the cleavage and inhibition of host TICAM1 CC (By similarity). Interacts with host TANK-binding kinase/TBK1; this CC interaction results in the inhibition of the association between TBK1 CC and IRF3, which leads to the inhibition of IRF3 activation (By CC similarity). Interacts with host RBM24 (By similarity). Part of the CC replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA- CC directed RNA polymerase embedded in an ER-derived membranous web (By CC similarity). Part of the viral assembly initiation complex composed of CC NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By CC similarity). {ECO:0000250|UniProtKB:P26663, CC ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8, CC ECO:0000250|UniProtKB:Q9WMX2}. CC -!- SUBUNIT: [Non-structural protein 4A]: Interacts with NS3 serine CC protease; this interaction stabilizes the folding of NS3 serine CC protease (By similarity). NS3-NS4A interaction is essential for NS3 CC activation and allows membrane anchorage of the latter (By similarity). CC Interacts with non-structural protein 5A (via N-terminus) CC (PubMed:8985418). Part of the replication complex composed of NS2, NS3, CC NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER- CC derived membranous web (By similarity). Part of the viral assembly CC initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the CC mature core protein (By similarity). {ECO:0000250|UniProtKB:P26663, CC ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8, CC ECO:0000269|PubMed:8985418}. CC -!- SUBUNIT: [Non-structural protein 4B]: Homomultimer (By similarity). CC Interacts with non-structural protein NS5A (By similarity). Interacts CC with host PLA2G4C; this interaction likely initiates the recruitment of CC replication complexes to lipid droplets (By similarity). Interacts with CC host STING; this interaction disrupts the interaction between STING and CC TBK1 thereby suppressing the interferon signaling (By similarity). Part CC of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and CC the RNA-directed RNA polymerase embedded in an ER-derived membranous CC web (By similarity). {ECO:0000250|UniProtKB:P27958, CC ECO:0000250|UniProtKB:Q99IB8}. CC -!- SUBUNIT: [Non-structural protein 5A]: Monomer (By similarity). CC Homodimer; dimerization is required for RNA-binding (Probable). CC Interacts with the mature core protein (By similarity). Interacts (via CC N-terminus) with non-structural protein 4A (PubMed:8985418). Interacts CC with non-structural protein 4B (By similarity). Interacts with RNA- CC directed RNA polymerase (By similarity). Part of the viral assembly CC initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the CC mature core protein (By similarity). Part of the replication complex CC composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA CC polymerase (By similarity). Interacts with host GRB2 (By similarity). CC Interacts with host BIN1 (By similarity). Interacts with host PIK3R1 CC (By similarity). Interacts with host SRCAP (By similarity). Interacts CC with host FKBP8 (PubMed:16844119). Interacts with host VAPB CC (PubMed:16227268). Interacts with host EIF2AK2/PKR; this interaction CC leads to disruption of EIF2AK2 dimerization by NS5A and probably allows CC the virus to evade the innate immune response (PubMed:17451199). CC Interacts (via N-terminus) with host PACSIN2 (via N-terminus); this CC interaction attenuates protein kinase C alpha-mediated phosphorylation CC of PACSIN2 by disrupting the interaction between PACSIN2 and PRKCA (By CC similarity). Interacts (via N-terminus) with host SRC kinase (via SH2 CC domain) (By similarity). Interacts with most Src-family kinases (By CC similarity). Interacts with host IFI27 and SKP2; promotes the CC ubiquitin-mediated proteasomal degradation of NS5A (By similarity). CC Interacts with host GPS2 (By similarity). Interacts with host TNFRSF21; CC this interaction allows the modulation by the virus of JNK, p38 MAPK, CC STAT3, and Akt signaling pathways in a DR6-dependent manner (By CC similarity). Interacts (via N-terminus) with host CIDEB (via N- CC terminus); this interaction seems to regulate the association of HCV CC particles with APOE (By similarity). Interacts with host CHKA/Choline CC Kinase-alpha; CHKA bridges host PI4KA and NS5A and potentiates NS5A- CC stimulated PI4KA activity, which then facilitates the targeting of the CC ternary complex to the ER for viral replication (By similarity). CC Interacts with host SPSB2 (via C-terminus); this interaction targets CC NS5A for ubiquitination and degradation (By similarity). Interacts with CC host RAB18; this interaction may promote the association of NS5A and CC other replicase components with lipid droplets (PubMed:23935497). 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 (By CC similarity). Interacts with host TRIM14; this interaction induces the CC degradation of NS5A (By similarity). {ECO:0000250|UniProtKB:P26663, CC ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958, CC ECO:0000250|UniProtKB:Q99IB8, ECO:0000269|PubMed:16227268, CC ECO:0000269|PubMed:16844119, ECO:0000269|PubMed:17451199, CC ECO:0000269|PubMed:23935497, ECO:0000269|PubMed:8985418, CC ECO:0000305|PubMed:31585734}. CC -!- SUBUNIT: [RNA-directed RNA polymerase]: Homooligomer (PubMed:11907226). CC Interacts with non-structural protein 5A (By similarity). Interacts CC with host VAPB (PubMed:16227268). Interacts with host PRK2/PKN2 CC (PubMed:25031343). Interacts with host HNRNPA1 and SEPT6; these CC interactions facilitate the viral replication (By similarity). Part of CC the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the CC RNA-directed RNA polymerase (By similarity). CC {ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:11907226, CC ECO:0000269|PubMed:16227268, ECO:0000269|PubMed:25031343}. CC -!- INTERACTION: CC PRO_0000037645; PRO_0000037644 [P26662]: -; NbExp=2; IntAct=EBI-8872853, EBI-8872843; CC PRO_0000037647; Q07812: BAX; Xeno; NbExp=3; IntAct=EBI-9099462, EBI-516580; CC PRO_0000037647; P62993: GRB2; Xeno; NbExp=3; IntAct=EBI-9099462, EBI-401755; CC -!- SUBCELLULAR LOCATION: [Core protein precursor]: Host endoplasmic CC reticulum membrane {ECO:0000269|PubMed:15163730, CC ECO:0000269|PubMed:15613354, ECO:0000305|PubMed:9621068}; Single-pass CC membrane protein {ECO:0000255}. Host mitochondrion membrane CC {ECO:0000269|PubMed:15613354}; Single-pass type I membrane protein CC {ECO:0000255}. Note=The C-terminal transmembrane domain of the core CC protein precursor contains an ER signal leading the nascent polyprotein CC to the ER membrane. CC -!- SUBCELLULAR LOCATION: [Mature core protein]: Virion CC {ECO:0000250|UniProtKB:Q99IB8}. Host cytoplasm CC {ECO:0000269|PubMed:9621068}. Host nucleus CC {ECO:0000269|PubMed:15163730, ECO:0000269|PubMed:15613354, CC ECO:0000269|PubMed:9621068}. Host lipid droplet CC {ECO:0000250|UniProtKB:Q99IB8}. Note=Only a minor proportion of core CC protein is present in the nucleus (By similarity). Probably present on CC the surface of lipid droplets (By similarity). CC {ECO:0000250|UniProtKB:P27958}. CC -!- SUBCELLULAR LOCATION: [Envelope glycoprotein E1]: Virion membrane CC {ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host CC endoplasmic reticulum membrane; Single-pass type I membrane protein CC {ECO:0000250|UniProtKB:P27958}. Note=The C-terminal transmembrane CC domain acts as a signal sequence and forms a hairpin structure before CC cleavage by host signal peptidase (By similarity). After cleavage, the CC membrane sequence is retained at the C-terminus of the protein, serving CC as ER membrane anchor (By similarity). A reorientation of the second CC hydrophobic stretch occurs after cleavage producing a single reoriented CC transmembrane domain (By similarity). These events explain the final CC topology of the protein (By similarity). CC {ECO:0000250|UniProtKB:P27958}. CC -!- SUBCELLULAR LOCATION: [Envelope glycoprotein E2]: Virion membrane CC {ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host CC endoplasmic reticulum membrane; Single-pass type I membrane protein CC {ECO:0000250|UniProtKB:P27958}. Host lipid droplet CC {ECO:0000250|UniProtKB:Q9WMX2}. Note=The C-terminal transmembrane CC domain acts as a signal sequence and forms a hairpin structure before CC cleavage by host signal peptidase (By similarity). After cleavage, the CC membrane sequence is retained at the C-terminus of the protein, serving CC as ER membrane anchor (By similarity). A reorientation of the second CC hydrophobic stretch occurs after cleavage producing a single reoriented CC transmembrane domain (By similarity). These events explain the final CC topology of the protein (By similarity). CC {ECO:0000250|UniProtKB:P27958}. CC -!- SUBCELLULAR LOCATION: [Viroporin p7]: Host endoplasmic reticulum CC membrane {ECO:0000250|UniProtKB:Q99IB8}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:Q99IB8}. Host mitochondrion CC {ECO:0000250|UniProtKB:P27958}. Host cell membrane CC {ECO:0000250|UniProtKB:Q99IB8}. 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:0000250|UniProtKB:Q99IB8}. Note=Probably present on the surface of CC lipid droplets. {ECO:0000250|UniProtKB:Q99IB8}. CC -!- SUBCELLULAR LOCATION: [Serine protease/helicase NS3]: Host endoplasmic CC reticulum membrane {ECO:0000305}; Peripheral membrane protein CC {ECO:0000305}. Note=NS3 is associated to the ER membrane through its CC binding to NS4A. {ECO:0000305}. CC -!- SUBCELLULAR LOCATION: [Non-structural protein 4A]: Host endoplasmic CC reticulum membrane {ECO:0000305}; Single-pass type I membrane protein CC {ECO:0000305}. Note=Host membrane insertion occurs after processing by CC the NS3 protease. {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:0000269|PubMed:16227268, CC ECO:0000269|PubMed:16844119}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:P27958}. Host cytoplasm, host perinuclear region CC {ECO:0000269|PubMed:7769656}. Host mitochondrion CC {ECO:0000269|PubMed:16844119}. Host cytoplasm CC {ECO:0000250|UniProtKB:P27958}. Host nucleus CC {ECO:0000269|PubMed:23468497}. Host lipid droplet CC {ECO:0000269|PubMed:23935497}. Note=Host membrane insertion occurs CC after processing by the NS3 protease (By similarity). Localizes at the CC surface of lipid droplets (PubMed:23935497). CC {ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:23935497}. CC -!- SUBCELLULAR LOCATION: [RNA-directed RNA polymerase]: Host cytoplasm CC {ECO:0000250|UniProtKB:P27958}. Host endoplasmic reticulum membrane; CC Single-pass type IV membrane protein {ECO:0000250|UniProtKB:P27958}. CC Note=Host membrane insertion occurs after processing by the NS3 CC protease. {ECO:0000250|UniProtKB:P27958}. CC -!- DOMAIN: [Envelope glycoprotein E1]: The transmembrane regions of CC envelope E1 and E2 glycoproteins are involved in heterodimer formation, CC ER localization, and assembly of these proteins. CC {ECO:0000250|UniProtKB:P27958}. CC -!- DOMAIN: [Envelope glycoprotein E2]: The transmembrane regions of CC envelope E1 and E2 glycoproteins are involved in heterodimer formation, CC ER localization, and assembly of these proteins (By similarity). CC Envelope E2 glycoprotein contain two highly variable regions called CC hypervariable region 1 and 2 (HVR1 and HVR2) (By similarity). E2 also CC contain two segments involved in CD81-binding (By similarity). HVR1 is CC implicated in the SCARB1-mediated cell entry and probably acts as a CC regulator of the association of particles with lipids (By similarity). CC {ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P27958}. CC -!- DOMAIN: [Protease NS2]: The N-terminus of NS3 is required for the CC catalytic activity of protease NS2 (By similarity). The minimal CC catalytic region includes the C-terminus of NS2 and the N-terminus NS3 CC protease domain (active region NS2-3) (By similarity). CC {ECO:0000250|UniProtKB:P26663}. CC -!- DOMAIN: [Serine protease/helicase NS3]: The N-terminal one-third of CC serine protease/helicase NS3 contains the protease activity CC (PubMed:9060645). This region contains a zinc atom that does not belong CC to the active site, but may play a structural rather than a catalytic CC role (PubMed:9060645). This region is essential for the activity of CC protease NS2, maybe by contributing to the folding of the latter CC (PubMed:9060645). The NTPase/helicase activity is located in the CC twothirds C-terminus of NS3, this domain contains the NTPase and RNA- CC binding regions (By similarity). {ECO:0000250|UniProtKB:P27958, CC ECO:0000269|PubMed:9060645}. CC -!- DOMAIN: [Non-structural protein 4B]: Contains a glycine zipper region CC that critically contributes to the biogenesis of functional ER-derived CC replication organelles. {ECO:0000250|UniProtKB:Q99IB8}. CC -!- DOMAIN: [Non-structural protein 5A]: The N-terminus of NS5A acts as CC membrane anchor (By similarity). The central part of NS5A contains a CC variable region called interferon sensitivity determining region (ISDR) CC and seems to be intrinsically disordered and interacts with NS5B and CC host EIF2AK2 (PubMed:9525599, PubMed:17451199). The C-terminus of NS5A CC contains a variable region called variable region 3 (V3) CC (PubMed:17451199). ISDR and V3 may be involved in sensitivity and/or CC resistance to IFN-alpha therapy (PubMed:9525599, PubMed:17451199). The CC C-terminus contains a nuclear localization signal (PubMed:23468497). CC The SH3-binding domain is involved in the interaction with host BIN1, CC GRB2 and Src-family kinases (By similarity). CC {ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:17451199, CC ECO:0000269|PubMed:23468497, ECO:0000269|PubMed:9525599}. 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 (PubMed:9621068, PubMed:15163730). Cleavage by the signal CC peptidase releases the 21 kDa mature core protein (PubMed:9621068, CC PubMed:15163730). The cleavage of the core protein precursor occurs CC between aminoacids 176 and 188 but the exact cleavage site is not known CC (By similarity). Some degraded forms of the core protein appear as well CC during the course of infection (By similarity). The other proteins (p7, CC NS2, NS3, NS4A, NS4B, NS5A and NS5B) are cleaved by the viral proteases CC (PubMed:8389908). Autoprocessing between NS2 and NS3 is mediated by the CC NS2 cysteine protease catalytic domain and regulated by the NS3 N- CC terminal domain (By similarity). {ECO:0000250|UniProtKB:P26663, CC ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8, CC ECO:0000269|PubMed:15163730, ECO:0000269|PubMed:8389908, CC ECO:0000269|PubMed:9621068}. CC -!- PTM: [Mature core protein]: Phosphorylated by host PKC and PKA. CC {ECO:0000250|UniProtKB:Q01403}. CC -!- PTM: [Mature core protein]: Ubiquitinated; mediated by UBE3A and CC leading to core protein subsequent proteasomal degradation. CC {ECO:0000250|UniProtKB:Q03463}. CC -!- PTM: [Envelope glycoprotein E1]: Highly N-glycosylated. CC {ECO:0000250|UniProtKB:P27958}. CC -!- PTM: [Envelope glycoprotein E2]: Highly N-glycosylated. CC {ECO:0000250|UniProtKB:P27958}. CC -!- PTM: [Protease NS2]: Palmitoylation is required for NS2/3 CC autoprocessing and E2 recruitment to membranes. CC {ECO:0000250|UniProtKB:P27958}. CC -!- PTM: [Non-structural protein 4B]: Palmitoylated. This modification may CC play a role in its polymerization or in protein-protein interactions. CC {ECO:0000250|UniProtKB:P27958}. CC -!- PTM: [Non-structural protein 5A]: Cleaved by host caspases which are CC probably activated by the viral infection. CC {ECO:0000269|PubMed:10793006, ECO:0000269|PubMed:16517592}. 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:7999043, PubMed:7769656). p58 is a CC hyperphosphorylated form of p56 (PubMed:7999043, PubMed:7769656). p56 CC and p58 coexist in the cell in roughly equivalent amounts CC (PubMed:7999043). Hyperphosphorylation is dependent on the presence of CC NS4A (PubMed:7999043). Host CSNK1A1/CKI-alpha or RPS6KB1 kinases may be CC responsible for NS5A phosphorylation (By similarity). Phosphorylated CC NS5A is involved in viral replication (By similarity). CC {ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:Q99IB8, CC ECO:0000269|PubMed:7769656, ECO:0000269|PubMed:7999043}. CC -!- PTM: [Non-structural protein 5A]: Tyrosine phosphorylation is essential CC for the interaction with host SRC. {ECO:0000250|UniProtKB:Q99IB8}. CC -!- PTM: [RNA-directed RNA polymerase]: The N-terminus is phosphorylated by CC host PRK2/PKN2. {ECO:0000269|PubMed:25031343}. 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:0000269|PubMed:8396658}. CC -!- SIMILARITY: Belongs to the hepacivirus polyprotein family. CC {ECO:0000305}. CC -!- CAUTION: The core gene probably also codes for alternative reading CC frame proteins (ARFPs). Many functions depicted for the core protein CC might belong to the ARFPs. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Virus Pathogen Resource; CC URL="https://www.viprbrc.org/brc/home.spg?decorator=flavi_hcv"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D90208; BAA14233.1; -; Genomic_RNA. DR EMBL; D89872; BAA14035.1; -; Genomic_RNA. DR EMBL; D11397; BAA20975.1; -; Genomic_RNA. DR PIR; A39253; GNWVCJ. DR PDB; 1DXP; X-ray; 2.40 A; A/B=1027-1213, C/D=1678-1691. DR PDB; 1DY8; X-ray; 2.40 A; A/B=1027-1213, C/D=1678-1692. DR PDB; 1DY9; X-ray; 2.10 A; A/B=1027-1213, C/D=1678-1692. DR PDB; 1W3C; X-ray; 2.30 A; A/B=1027-1213, C/D=1678-1692. DR PDB; 2K8J; NMR; -; X=781-809. DR PDB; 3OYP; X-ray; 2.76 A; A/B=1027-1213, C/D=1678-1691. DR PDB; 3P8N; X-ray; 1.90 A; A/B=1027-1206, C/D=1678-1691. DR PDB; 3P8O; X-ray; 2.30 A; A/B=1027-1206, C/D=1678-1691. DR PDB; 4A1T; X-ray; 2.05 A; A/B=1028-1206, A/B=1678-1690. DR PDB; 4A1V; X-ray; 2.20 A; A/B=1028-1206, A/B=1678-1690. DR PDB; 4A1X; X-ray; 1.90 A; A/B=1028-1206. DR PDB; 4I31; X-ray; 1.93 A; A/B=1027-1206, C/D=1678-1691. DR PDB; 4I32; X-ray; 2.30 A; A/B=1027-1206, C/D=1678-1691. DR PDB; 4I33; X-ray; 1.90 A; A/B=1027-1206, C/D=1678-1691. DR PDB; 4JMY; X-ray; 1.95 A; C/D=1678-1691. DR PDB; 4KTC; X-ray; 2.30 A; A/C=1028-1213. DR PDBsum; 1DXP; -. DR PDBsum; 1DY8; -. DR PDBsum; 1DY9; -. DR PDBsum; 1W3C; -. DR PDBsum; 2K8J; -. DR PDBsum; 3OYP; -. DR PDBsum; 3P8N; -. DR PDBsum; 3P8O; -. DR PDBsum; 4A1T; -. DR PDBsum; 4A1V; -. DR PDBsum; 4A1X; -. DR PDBsum; 4I31; -. DR PDBsum; 4I32; -. DR PDBsum; 4I33; -. DR PDBsum; 4JMY; -. DR PDBsum; 4KTC; -. DR BMRB; P26662; -. DR SMR; P26662; -. DR ELM; P26662; -. DR IntAct; P26662; 5. DR MINT; P26662; -. DR BindingDB; P26662; -. DR ChEMBL; CHEMBL3988603; -. DR DrugBank; DB01720; (2Z)-2-(Benzoylamino)-3-[4-(2-bromophenoxy)phenyl]acrylic acid. DR DrugBank; DB04005; Uridine 5'-triphosphate. DR MEROPS; S29.001; -. DR GlyGen; P26662; 19 sites. DR iPTMnet; P26662; -. DR ABCD; P26662; 7 sequenced antibodies. DR euHCVdb; D89872; -. DR euHCVdb; D90208; -. DR BRENDA; 3.4.21.98; 17002. DR SABIO-RK; P26662; -. DR EvolutionaryTrace; P26662; -. DR Proteomes; UP000008095; Segment. DR Proteomes; UP000165187; Genome. DR GO; GO:0044167; C:host cell endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0044186; C:host cell lipid droplet; IEA:UniProtKB-SubCell. DR GO; GO:0044191; C:host cell mitochondrial membrane; IEA:UniProtKB-SubCell. DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW. DR GO; GO:0032993; C:protein-DNA complex; IMP:CAFA. DR GO; GO:1990904; C:ribonucleoprotein complex; IMP:CAFA. DR GO; GO:0019031; C:viral envelope; IEA:UniProtKB-KW. DR GO; GO:0019013; C:viral nucleocapsid; IEA:UniProtKB-KW. DR GO; GO:0055036; C:virion membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IEA:RHEA. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro. DR GO; GO:0003677; F:DNA binding; IMP:CAFA. DR GO; GO:1990814; F:DNA/DNA annealing activity; IMP:CAFA. DR GO; GO:0005216; F:monoatomic ion channel activity; IEA:UniProtKB-KW. DR GO; GO:0003723; F:RNA binding; IMP:CAFA. DR GO; GO:0140691; F:RNA folding chaperone; IDA:DisProt. DR GO; GO:0003724; F:RNA helicase activity; IDA:CACAO. DR GO; GO:0033592; F:RNA strand annealing activity; IMP:CAFA. DR GO; GO:0003968; F:RNA-dependent RNA polymerase activity; IEA:UniProtKB-KW. DR GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro. DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0075512; P:clathrin-dependent endocytosis of virus by host cell; IEA:UniProtKB-KW. DR GO; GO:0039563; P:disruption by virus of host JAK-STAT cascade via inhibition of STAT1 activity; IEA:UniProtKB-KW. DR GO; GO:0039527; P:disruption by virus of host TRAF-mediated signal transduction; IEA:UniProtKB-KW. DR GO; GO:0039654; P:fusion of virus membrane with host endosome membrane; IEA:UniProtKB-KW. DR GO; GO:0039520; P:induction by virus of host autophagy; IEA:UniProtKB-KW. DR GO; GO:0039645; P:perturbation by virus of host G1/S transition checkpoint; IEA:UniProtKB-KW. DR GO; GO:0051259; P:protein complex oligomerization; IEA:UniProtKB-KW. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR GO; GO:0043489; P:RNA stabilization; IMP:CAFA. DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW. DR GO; GO:0039545; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity; IEA:UniProtKB-KW. DR GO; GO:0019087; P:transformation of host cell by virus; IEA:InterPro. DR GO; GO:0039694; P:viral RNA genome replication; IEA:InterPro. DR GO; GO:0019062; P:virion attachment to host cell; IEA:UniProtKB-KW. DR GO; GO:0039707; P:virus-mediated pore formation in host cell membrane; IEA:UniProtKB-KW. DR CDD; cd17931; DEXHc_viral_Ns3; 1. DR CDD; cd20903; HCV_p7; 1. DR CDD; cd23202; Hepacivirus_RdRp; 1. DR Gene3D; 2.40.10.120; -; 1. DR Gene3D; 3.30.70.270; -; 2. DR Gene3D; 6.10.250.1610; -; 1. DR Gene3D; 6.10.250.1750; -; 1. DR Gene3D; 6.10.250.2920; -; 1. DR Gene3D; 2.20.25.210; Hepatitis C NS5A, domain 1B; 1. DR Gene3D; 3.30.160.890; Hepatitis C virus envelope glycoprotein E1, chain C; 1. DR Gene3D; 2.30.30.710; Hepatitis C virus non-structural protein NS2, C-terminal domain; 1. DR Gene3D; 1.20.1280.150; Hepatitis C virus non-structural protein NS2, N-terminal domain; 1. DR Gene3D; 2.20.25.220; Hepatitis C virus NS5A, 1B domain; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR Gene3D; 1.10.820.10; RNA Helicase Chain A , domain 3; 1. DR Gene3D; 2.40.10.10; Trypsin-like serine proteases; 1. DR InterPro; IPR043502; DNA/RNA_pol_sf. DR InterPro; IPR011492; Flavi_DEAD. DR InterPro; IPR002521; HCV_Core_C. DR InterPro; IPR044896; HCV_core_chain_A. DR InterPro; IPR002522; HCV_core_N. DR InterPro; IPR002519; HCV_Env. DR InterPro; IPR002531; HCV_NS1. DR InterPro; IPR002518; HCV_NS2. DR InterPro; IPR042205; HCV_NS2_C. DR InterPro; IPR042209; HCV_NS2_N. DR InterPro; IPR000745; HCV_NS4a. DR InterPro; IPR001490; HCV_NS4b. DR InterPro; IPR002868; HCV_NS5a. DR InterPro; IPR013192; HCV_NS5A_1a. DR InterPro; IPR013193; HCV_NS5a_1B_dom. DR InterPro; IPR038568; HCV_NS5A_1B_sf. DR InterPro; IPR024350; HCV_NS5a_C. DR InterPro; IPR014001; Helicase_ATP-bd. DR InterPro; IPR001650; Helicase_C. DR InterPro; IPR004109; HepC_NS3_protease. DR InterPro; IPR038170; NS5A_1a_sf. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin. DR InterPro; IPR043128; Rev_trsase/Diguanyl_cyclase. DR InterPro; IPR007094; RNA-dir_pol_PSvirus. DR InterPro; IPR002166; RNA_pol_HCV. DR Pfam; PF07652; Flavi_DEAD; 1. DR Pfam; PF01543; HCV_capsid; 1. DR Pfam; PF01542; HCV_core; 1. DR Pfam; PF01539; HCV_env; 1. DR Pfam; PF01560; HCV_NS1; 1. DR Pfam; PF01538; HCV_NS2; 1. DR Pfam; PF01006; HCV_NS4a; 1. DR Pfam; PF01001; HCV_NS4b; 1. DR Pfam; PF01506; HCV_NS5a; 1. DR Pfam; PF08300; HCV_NS5a_1a; 1. DR Pfam; PF08301; HCV_NS5a_1b; 1. DR Pfam; PF12941; HCV_NS5a_C; 1. DR Pfam; PF02907; Peptidase_S29; 1. DR Pfam; PF00998; RdRP_3; 1. DR SMART; SM00487; DEXDc; 1. DR SMART; SM00490; HELICc; 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; Thiol protease; KW Transcription; Transcription regulation; Transferase; Transmembrane; KW Transmembrane helix; Transport; Ubl conjugation; KW Viral attachment to host cell; Viral envelope protein; Viral immunoevasion; KW Viral ion channel; Viral nucleoprotein; KW Viral penetration into host cytoplasm; Viral RNA replication; Virion; KW Virus endocytosis by host; Virus entry into host cell; Zinc. FT INIT_MET 1 FT /note="Removed; by host" FT /evidence="ECO:0000250|UniProtKB:P26664" FT CHAIN 2..3010 FT /note="Genome polyprotein" FT /id="PRO_0000450855" FT CHAIN 2..191 FT /note="Core protein precursor" FT /id="PRO_0000037637" FT CHAIN 2..177 FT /note="Mature core protein" FT /id="PRO_0000037638" FT PROPEP 178..191 FT /note="ER anchor for the core protein, removed in mature FT form by host signal peptidase" FT /evidence="ECO:0000269|PubMed:15163730" FT /id="PRO_0000037639" FT CHAIN 192..383 FT /note="Envelope glycoprotein E1" FT /id="PRO_0000037640" FT CHAIN 384..746 FT /note="Envelope glycoprotein E2" FT /id="PRO_0000037641" FT CHAIN 747..809 FT /note="Viroporin p7" FT /id="PRO_0000037642" FT CHAIN 810..1026 FT /note="Protease NS2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030" FT /id="PRO_0000037643" FT CHAIN 1027..1657 FT /note="Serine protease/helicase NS3" FT /id="PRO_0000037644" FT CHAIN 1658..1711 FT /note="Non-structural protein 4A" FT /id="PRO_0000037645" FT CHAIN 1712..1972 FT /note="Non-structural protein 4B" FT /id="PRO_0000037646" FT CHAIN 1973..2419 FT /note="Non-structural protein 5A" FT /id="PRO_0000037647" FT CHAIN 2420..3010 FT /note="RNA-directed RNA polymerase" FT /id="PRO_0000037648" FT TOPO_DOM 2..168 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 169..189 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 190..358 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TRANSMEM 359..379 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TOPO_DOM 380..725 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TRANSMEM 726..746 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TOPO_DOM 747..757 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TRANSMEM 758..778 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TOPO_DOM 779..781 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TRANSMEM 782..803 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TOPO_DOM 804..813 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TRANSMEM 814..834 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT TOPO_DOM 835..838 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT TRANSMEM 839..859 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT TOPO_DOM 860..881 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT TRANSMEM 882..902 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT TOPO_DOM 903..1657 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT TRANSMEM 1658..1678 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1679..1805 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 1806..1826 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1827..1828 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 1829..1849 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1850 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 1851..1871 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1872..1881 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 1882..1902 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1903..1972 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT INTRAMEM 1973..2002 FT /evidence="ECO:0000250|UniProtKB:P27958" FT TOPO_DOM 2003..2989 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P27958" FT TRANSMEM 2990..3010 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P27958" FT DOMAIN 903..1026 FT /note="Peptidase C18" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030" FT DOMAIN 1027..1208 FT /note="Peptidase S29" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166" FT DOMAIN 1217..1369 FT /note="Helicase ATP-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541" FT DOMAIN 2633..2751 FT /note="RdRp catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00539" FT REGION 2..75 FT /note="Disordered" FT /evidence="ECO: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:0000269|PubMed:17267064" FT REGION 2..23 FT /note="Interaction with STAT1" FT /evidence="ECO:0000269|PubMed:16940534" FT REGION 112..152 FT /note="Important for endoplasmic reticulum and FT mitochondrial localization" FT /evidence="ECO:0000269|PubMed:15613354" FT REGION 122..173 FT /note="Interaction with APOA2" FT /evidence="ECO:0000250|UniProtKB:P29846" FT REGION 164..167 FT /note="Important for lipid droplets localization" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 265..296 FT /note="Important for fusion" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 385..411 FT /note="HVR1" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 474..482 FT /note="HVR2" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 480..493 FT /note="CD81-binding 1" FT /evidence="ECO:0000250|UniProtKB:P26663" FT REGION 544..551 FT /note="CD81-binding 2" FT /evidence="ECO:0000250|UniProtKB:P26663" FT REGION 660..671 FT /note="EIF2AK2/eIF2-alpha phosphorylation homology domain FT (PePHD)" FT REGION 904..1206 FT /note="Protease NS2-3" FT /evidence="ECO:0000250|UniProtKB:P26663" FT REGION 929..949 FT /note="Interaction with host SCPS1" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT REGION 1486..1497 FT /note="RNA-binding" FT /evidence="ECO:0000250|UniProtKB:P26663" FT REGION 1679..1690 FT /note="NS3-binding" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 1833..1861 FT /note="Glycine zipper" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT REGION 1978..1998 FT /note="Membrane-binding" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 2005..2221 FT /note="RNA-binding" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 2120..2332 FT /note="Transcriptional activation" FT /evidence="ECO:0000255" FT REGION 2120..2208 FT /note="FKBP8-binding" FT /evidence="ECO:0000269|PubMed:16844119" FT REGION 2135..2139 FT /note="Interaction with non-structural protein 4A" FT /evidence="ECO:0000269|PubMed:8985418" FT REGION 2187..2219 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2189..2441 FT /note="Interaction with host SKP2" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 2206..2245 FT /note="ISDR" FT /evidence="ECO:0000269|PubMed:9525599" FT REGION 2210..2275 FT /note="EIF2AK2/PKR-binding" FT /evidence="ECO:0000255" FT REGION 2210..2249 FT /note="ISDR" FT /evidence="ECO:0000269|PubMed:9525599" FT REGION 2249..2306 FT /note="NS4B-binding" FT /evidence="ECO:0000255" FT REGION 2332..2441 FT /note="Interaction with host IFI27" FT /evidence="ECO:0000250|UniProtKB:P27958" FT REGION 2351..2408 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2354..2377 FT /note="V3" FT MOTIF 5..13 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT MOTIF 38..43 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT MOTIF 58..64 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT MOTIF 66..71 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT MOTIF 1316..1319 FT /note="DECH box" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT MOTIF 2322..2325 FT /note="SH3-binding" FT /evidence="ECO:0000255" FT MOTIF 2326..2334 FT /note="Nuclear localization signal" FT /evidence="ECO:0000269|PubMed:23468497, FT ECO:0000305|PubMed:10793006" FT COMPBIAS 47..69 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2195..2217 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2351..2369 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 952 FT /note="For protease NS2 activity; shared with dimeric FT partner" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030" FT ACT_SITE 972 FT /note="For protease NS2 activity; shared with dimeric FT partner" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030" FT ACT_SITE 993 FT /note="For protease NS2 activity; shared with dimeric FT partner" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030, FT ECO:0000305|PubMed:8392606" FT ACT_SITE 1083 FT /note="Charge relay system; for serine protease NS3 FT activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, FT ECO:0000305|PubMed:8389908, ECO:0000305|PubMed:8392606, FT ECO:0000305|PubMed:9060645" FT ACT_SITE 1107 FT /note="Charge relay system; for serine protease NS3 FT activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, FT ECO:0000305|PubMed:8389908, ECO:0000305|PubMed:8392606" FT ACT_SITE 1165 FT /note="Charge relay system; for serine protease NS3 FT activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166" FT BINDING 1123 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="structural; for NS3 protease activity and FT NS2/3 auto-cleavage activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, FT ECO:0000269|PubMed:9060645" FT BINDING 1125 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="structural; for NS3 protease activity and FT NS2/3 auto-cleavage activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, FT ECO:0000269|PubMed:9060645" FT BINDING 1171 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="structural; for NS3 protease activity and FT NS2/3 auto-cleavage activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, FT ECO:0000269|PubMed:9060645" FT BINDING 1175 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="structural; for NS3 protease activity and FT NS2/3 auto-cleavage activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, FT ECO:0000269|PubMed:9060645" FT BINDING 1230..1237 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541" FT BINDING 1237 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic; for NS3 helicase activity" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT BINDING 1317 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic; for NS3 helicase activity" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT BINDING 2011 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="structural" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT BINDING 2029 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="structural" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT BINDING 2031 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="structural" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT BINDING 2052 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="structural" FT /evidence="ECO:0000250|UniProtKB:Q9WMX2" FT BINDING 2639 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic; for RNA-directed RNA polymerase FT activity" FT /evidence="ECO:0000250|UniProtKB:P26663" FT BINDING 2737 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic; for RNA-directed RNA polymerase FT activity" FT /evidence="ECO:0000250|UniProtKB:P26663" FT BINDING 2738 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic; for RNA-directed RNA polymerase FT activity" FT /evidence="ECO:0000250|UniProtKB:P26663" FT SITE 177..178 FT /note="Cleavage; by signal peptide peptidase" FT /evidence="ECO:0000305|PubMed:15163730" FT SITE 191..192 FT /note="Cleavage; by host signal peptidase" FT /evidence="ECO:0000269|PubMed:1648221, FT ECO:0000269|PubMed:9621068" FT SITE 383..384 FT /note="Cleavage; by host signal peptidase" FT /evidence="ECO:0000269|PubMed:1648221" FT SITE 746..747 FT /note="Cleavage; by host signal peptidase" FT /evidence="ECO:0000250" FT SITE 809..810 FT /note="Cleavage; by host signal peptidase" FT /evidence="ECO:0000250" FT SITE 1026..1027 FT /note="Cleavage; by protease NS2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01030" FT SITE 1657..1658 FT /note="Cleavage; by serine protease/helicase NS3" FT /evidence="ECO:0000250|UniProtKB:P27958" FT SITE 1711..1712 FT /note="Cleavage; by serine protease/helicase NS3" FT /evidence="ECO:0000250|UniProtKB:P27958" FT SITE 1972..1973 FT /note="Cleavage; by serine protease/helicase NS3" FT /evidence="ECO:0000250|UniProtKB:P27958" FT SITE 2419..2420 FT /note="Cleavage; by serine protease/helicase NS3" FT /evidence="ECO:0000250|UniProtKB:P27958" FT MOD_RES 2 FT /note="N-acetylserine; by host" FT /evidence="ECO:0000250|UniProtKB:Q913V3" FT MOD_RES 53 FT /note="Phosphoserine; by host" FT /evidence="ECO:0000250|UniProtKB:Q01403" FT MOD_RES 99 FT /note="Phosphoserine; by host" FT /evidence="ECO:0000250|UniProtKB:Q01403" FT MOD_RES 116 FT /note="Phosphoserine; by host PKA" FT /evidence="ECO:0000250|UniProtKB:Q01403" FT MOD_RES 2194 FT /note="Phosphoserine; by host; in p56" FT /evidence="ECO:0000269|PubMed:7769656" FT MOD_RES 2197 FT /note="Phosphoserine; by host; in p58" FT /evidence="ECO:0000269|PubMed:7769656" FT MOD_RES 2201 FT /note="Phosphoserine; by host; in p58" FT /evidence="ECO:0000269|PubMed:7769656" FT MOD_RES 2204 FT /note="Phosphoserine; by host; in p58" FT /evidence="ECO:0000269|PubMed:7769656" FT MOD_RES 2207 FT /note="Phosphoserine; by host; in p58" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT MOD_RES 2210 FT /note="Phosphoserine; by host; in p58" FT /evidence="ECO:0000250|UniProtKB:Q99IB8" FT MOD_RES 2448 FT /note="Phosphoserine; by host" FT /evidence="ECO:0000269|PubMed:25031343" FT MOD_RES 2461 FT /note="Phosphoserine; by host" FT /evidence="ECO:0000269|PubMed:25031343" FT LIPID 922 FT /note="S-palmitoyl cysteine; by host" FT /evidence="ECO:0000250|UniProtKB:P27958" FT LIPID 1968 FT /note="S-palmitoyl cysteine; by host" FT /evidence="ECO:0000250|UniProtKB:P27958" FT LIPID 1972 FT /note="S-palmitoyl cysteine; by host" FT /evidence="ECO:0000250|UniProtKB:P27958" FT CARBOHYD 196 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO: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 385 FT /note="O-linked (Hex...) threonine; by host" FT /evidence="ECO:0000305|PubMed:23242014" FT CARBOHYD 396 FT /note="O-linked (Hex...) threonine; by host" FT /evidence="ECO:0000269|PubMed:23242014" FT CARBOHYD 401 FT /note="O-linked (Hex...) serine; by host" FT /evidence="ECO:0000269|PubMed:23242014" FT CARBOHYD 404 FT /note="O-linked (Hex...) serine; by host" FT /evidence="ECO:0000269|PubMed:23242014" 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 473 FT /note="O-linked (Hex...) threonine; by host" FT /evidence="ECO:0000269|PubMed:23242014" FT CARBOHYD 518 FT /note="O-linked (Hex...) threonine; by host" FT /evidence="ECO:0000269|PubMed:23242014" FT CARBOHYD 532 FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by FT host" FT /evidence="ECO:0000250|UniProtKB:P27958" FT CARBOHYD 556 FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by FT host" FT /evidence="ECO:0000250|UniProtKB:P27958" FT CARBOHYD 576 FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by FT host" FT /evidence="ECO:0000250|UniProtKB:P27958" FT CARBOHYD 623 FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by FT host" FT /evidence="ECO:0000250|UniProtKB:P27958" FT CARBOHYD 645 FT /note="N-linked (GlcNAc...) (high mannose) asparagine; by FT host" FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 429..552 FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 452..459 FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 486..494 FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 503..508 FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 564..569 FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 581..585 FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 597..620 FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 607..644 FT /evidence="ECO:0000250|UniProtKB:P27958" FT DISULFID 652..677 FT /evidence="ECO:0000250|UniProtKB:P27958" FT CROSSLNK 2350 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P27958" FT VARIANT 464 FT /note="E -> K" FT VARIANT 475..479 FT /note="DMPES -> VVPNI" FT VARIANT 492 FT /note="R -> Q" FT VARIANT 522..524 FT /note="FGA -> SGV" FT VARIANT 538..540 FT /note="LLS -> VLN" FT VARIANT 580 FT /note="V -> I" FT VARIANT 608 FT /note="M -> L" FT VARIANT 622 FT /note="V -> I" FT VARIANT 626 FT /note="V -> I" FT VARIANT 674 FT /note="I -> V" FT VARIANT 694 FT /note="R -> Q" FT VARIANT 705 FT /note="I -> V" FT VARIANT 708 FT /note="A -> V" FT VARIANT 712..713 FT /note="FA -> VV" FT VARIANT 719 FT /note="I -> V" FT VARIANT 906 FT /note="I -> M" FT VARIANT 983 FT /note="L -> I" FT VARIANT 1140 FT /note="V -> I" FT VARIANT 1158 FT /note="I -> V" FT VARIANT 1252 FT /note="L -> R" FT VARIANT 1297 FT /note="C -> G" FT VARIANT 1323 FT /note="S -> W" FT VARIANT 1477 FT /note="L -> V" FT VARIANT 1485 FT /note="A -> S" FT VARIANT 1536 FT /note="S -> T" FT VARIANT 1583 FT /note="L -> F" FT VARIANT 1635 FT /note="V -> I" FT VARIANT 1644..1645 FT /note="YI -> FV" FT VARIANT 1695 FT /note="I -> V" FT VARIANT 1703 FT /note="Q -> R" FT VARIANT 1710 FT /note="E -> A" FT VARIANT 1713 FT /note="S -> P" FT VARIANT 1753 FT /note="K -> R" FT VARIANT 1759 FT /note="V -> A" FT VARIANT 1839 FT /note="V -> I" FT VARIANT 1873 FT /note="M -> A" FT VARIANT 1876 FT /note="T -> A" FT VARIANT 1896 FT /note="V -> I" FT VARIANT 1978 FT /note="K -> R" FT VARIANT 1989 FT /note="S -> T" FT VARIANT 2002 FT /note="R -> K" FT VARIANT 2006 FT /note="L -> V" FT VARIANT 2009 FT /note="L -> F" FT VARIANT 2093 FT /note="V -> I" FT VARIANT 2125 FT /note="V -> L" FT VARIANT 2136..2138 FT /note="VCK -> ACR" FT VARIANT 2143..2146 FT /note="EEVV -> VDVT" FT VARIANT 2190 FT /note="L -> P" FT VARIANT 2196 FT /note="P -> S" FT VARIANT 2199 FT /note="A -> G" FT VARIANT 2199 FT /note="A -> V" FT VARIANT 2200 FT /note="S -> T" FT VARIANT 2204 FT /note="S -> R" FT VARIANT 2205 FT /note="Q -> H" FT VARIANT 2208 FT /note="A -> T" FT VARIANT 2209 FT /note="P -> H" FT VARIANT 2209 FT /note="P -> L" FT VARIANT 2209 FT /note="P -> S" FT VARIANT 2210 FT /note="S -> P" FT VARIANT 2211 FT /note="L -> S" FT VARIANT 2212 FT /note="K -> E" FT VARIANT 2212 FT /note="K -> R" FT VARIANT 2214 FT /note="T -> A" FT VARIANT 2215 FT /note="C -> Y" FT VARIANT 2216 FT /note="T -> I" FT VARIANT 2217 FT /note="T -> A" FT VARIANT 2218 FT /note="H -> A" FT VARIANT 2218 FT /note="H -> L" FT VARIANT 2218 FT /note="H -> Q" FT VARIANT 2218 FT /note="H -> R" FT VARIANT 2218 FT /note="H -> T" FT VARIANT 2219 FT /note="H -> R" FT VARIANT 2219 FT /note="H -> Y" FT VARIANT 2220 FT /note="D -> G" FT VARIANT 2222 FT /note="P -> L" FT VARIANT 2222 FT /note="P -> S" FT VARIANT 2223 FT /note="D -> G" FT VARIANT 2224 FT /note="A -> V" FT VARIANT 2225 FT /note="D -> G" FT VARIANT 2225 FT /note="D -> N" FT VARIANT 2227 FT /note="I -> V" FT VARIANT 2228 FT /note="E -> A" FT VARIANT 2228 FT /note="E -> D" FT VARIANT 2228 FT /note="E -> G" FT VARIANT 2228 FT /note="E -> K" FT VARIANT 2230 FT /note="N -> D" FT VARIANT 2230 FT /note="N -> S" FT VARIANT 2233 FT /note="W -> R" FT VARIANT 2259 FT /note="I -> L" FT VARIANT 2262 FT /note="V -> E" FT VARIANT 2268 FT /note="I -> V" FT VARIANT 2271 FT /note="P -> A" FT VARIANT 2278..2279 FT /note="PR -> SK" FT VARIANT 2303 FT /note="D -> S" FT VARIANT 2310 FT /note="V -> A" FT VARIANT 2318..2321 FT /note="STKA -> PTTG" FT VARIANT 2329 FT /note="R -> K" FT VARIANT 2367 FT /note="G -> A" FT VARIANT 2372 FT /note="A -> T" FT VARIANT 2379 FT /note="G -> E" FT VARIANT 2382 FT /note="V -> I" FT VARIANT 2414..2416 FT /note="EDV -> DDI" FT VARIANT 2673 FT /note="R -> K" FT VARIANT 2681 FT /note="V -> I" FT VARIANT 2754 FT /note="A -> S" FT VARIANT 2757 FT /note="A -> V" FT VARIANT 2950 FT /note="K -> R" FT MUTAGEN 139 FT /note="L->A: Complete loss of core protein processing by FT host signal peptidase, no effect on the cleavage at core-E1 FT junction; when associated with A-140 and A-144." FT /evidence="ECO:0000269|PubMed:15163730" FT MUTAGEN 140 FT /note="V->A: Complete loss of core protein processing by FT host signal peptidase, no effect on the cleavage at core-E1 FT junction; when associated with A-139 and A-144." FT /evidence="ECO:0000269|PubMed:15163730" FT MUTAGEN 144 FT /note="L->A: Complete loss of core protein processing by FT host signal peptidase, no effect on the cleavage at core-E1 FT junction; when associated with A-139 and A-140." FT /evidence="ECO:0000269|PubMed:15163730" FT MUTAGEN 176..177 FT /note="IF->AL: Complete loss of core protein processing by FT host signal peptidase." FT /evidence="ECO:0000269|PubMed:15163730" FT MUTAGEN 178..179 FT /note="LL->VV: No effect on processing of the core FT protein." FT /evidence="ECO:0000269|PubMed:15163730" FT MUTAGEN 181..182 FT /note="LL->VV: No effect on processing of the core FT protein." FT /evidence="ECO:0000269|PubMed:15163730" FT MUTAGEN 183..184 FT /note="SC->LA: No effect on processing of the core FT protein." FT /evidence="ECO:0000269|PubMed:15163730" FT MUTAGEN 183..184 FT /note="SC->LV: No effect on processing of the core FT protein." FT /evidence="ECO:0000269|PubMed:15163730" FT MUTAGEN 922 FT /note="C->A: No effect on polyprotein processing." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 932 FT /note="H->A: No effect on polyprotein processing." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 952 FT /note="H->A,R: Complete loss of protease NS2 activity." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 972 FT /note="E->Q: Reduced protease NS2 activity." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 980 FT /note="E->Q: No effect on polyprotein processing." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 993 FT /note="C->A: Complete loss of protease NS2 activity." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 1009 FT /note="E->Q: No effect on polyprotein processing." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 1042 FT /note="C->A: No effect on zinc-binding by serine protease FT NS3." FT /evidence="ECO:0000269|PubMed:9060645" FT MUTAGEN 1058 FT /note="E->Q: No effect on polyprotein processing." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 1073 FT /note="C->S: No effect on zinc-binding by serine protease FT NS3." FT /evidence="ECO:0000269|PubMed:9060645" FT MUTAGEN 1078 FT /note="C->L: No effect on zinc-binding by serine protease FT NS3." FT /evidence="ECO:0000269|PubMed:9060645" FT MUTAGEN 1083 FT /note="H->A: Complete loss of serine protease NS3 activity. FT No effect on zinc-binding by serine protease NS3." FT /evidence="ECO:0000269|PubMed:8389908, FT ECO:0000269|PubMed:8392606, ECO:0000269|PubMed:9060645" FT MUTAGEN 1107 FT /note="D->A: Complete loss of serine protease NS3 FT activity." FT /evidence="ECO:0000269|PubMed:8389908, FT ECO:0000269|PubMed:8392606" FT MUTAGEN 1123 FT /note="C->A: Reduced protease NS2 and serine protease NS3 FT activities." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 1125 FT /note="C->A: Reduced protease NS2 and serine protease NS3 FT activities." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 1136 FT /note="H->A: No effect on polyprotein processing. No effect FT on zinc-binding by serine protease/helicase NS3." FT /evidence="ECO:0000269|PubMed:8392606, FT ECO:0000269|PubMed:9060645" FT MUTAGEN 1165 FT /note="S->A: Complete loss of serine protease NS3 activity. FT No effect on zinc-binding by serine protease NS3." FT /evidence="ECO:0000269|PubMed:8389908, FT ECO:0000269|PubMed:8392606, ECO:0000269|PubMed:9060645" FT MUTAGEN 1171 FT /note="C->A: Reduced protease NS2 and serine protease NS3 FT activities." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 1175 FT /note="H->A: No effect on polyprotein processing. Reduces FT zinc-binding by serine protease NS3." FT /evidence="ECO:0000269|PubMed:8392606, FT ECO:0000269|PubMed:9060645" FT MUTAGEN 1185 FT /note="C->A: No effect on polyprotein processing. No effect FT on zinc-binding by serine protease NS3." FT /evidence="ECO:0000269|PubMed:8392606, FT ECO:0000269|PubMed:9060645" FT MUTAGEN 1199 FT /note="E->Q: No effect on polyprotein processing." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 1202 FT /note="E->Q: No effect on polyprotein processing." FT /evidence="ECO:0000269|PubMed:8392606" FT MUTAGEN 1227 FT /note="H->A: No effect on polyprotein processing. No effect FT on zinc-binding by serine protease NS3." FT /evidence="ECO:0000269|PubMed:8392606, FT ECO:0000269|PubMed:9060645" FT MUTAGEN 1229 FT /note="H->A: No effect on polyprotein processing. No effect FT on zinc-binding by serine protease NS3." FT /evidence="ECO:0000269|PubMed:8392606, FT ECO:0000269|PubMed:9060645" FT MUTAGEN 2126 FT /note="D->E: Complete loss of nuclear translocation of FT NS5A." FT /evidence="ECO:0000269|PubMed:23468497" FT MUTAGEN 2194 FT /note="S->A: No effect on NS5A hyperphosphorylation and on FT down-regulation of viral translation." FT /evidence="ECO:0000269|PubMed:31585734, FT ECO:0000269|PubMed:7769656" FT MUTAGEN 2194 FT /note="S->D: No effect on down-regulation of viral FT translation." FT /evidence="ECO:0000269|PubMed:31585734" FT MUTAGEN 2197 FT /note="S->A: Loss of NS5A hyperphosphorylation; no effect FT on down-regulation of viral translation." FT /evidence="ECO:0000269|PubMed:31585734, FT ECO:0000269|PubMed:7769656" FT MUTAGEN 2197 FT /note="S->D: No effect on down-regulation of viral FT translation." FT /evidence="ECO:0000269|PubMed:31585734" FT MUTAGEN 2200 FT /note="S->A: No effect on NS5A hyperphosphorylation." FT /evidence="ECO:0000269|PubMed:7769656" FT MUTAGEN 2201 FT /note="S->A: Loss of NS5A hyperphosphorylation. Complete FT loss of NS5A-induced down-regulation of viral translation." FT /evidence="ECO:0000269|PubMed:31585734, FT ECO:0000269|PubMed:7769656" FT MUTAGEN 2201 FT /note="S->D: No effect on down-regulation of viral FT translation; increased NS5A dimerization." FT /evidence="ECO:0000269|PubMed:31585734" FT MUTAGEN 2202 FT /note="S->A: No effect on NS5A hyperphosphorylation." FT /evidence="ECO:0000269|PubMed:7769656" FT MUTAGEN 2204 FT /note="S->A: Loss of NS5A hyperphosphorylation. No effect FT on down-regulation of viral translation." FT /evidence="ECO:0000269|PubMed:31585734, FT ECO:0000269|PubMed:7769656" FT MUTAGEN 2204 FT /note="S->D: Complete loss of NS5A-induced down-regulation FT of viral translation." FT /evidence="ECO:0000269|PubMed:31585734" FT MUTAGEN 2207 FT /note="S->A: No effect on NS5A hyperphosphorylation. No FT effect on down-regulation of viral translation." FT /evidence="ECO:0000269|PubMed:31585734, FT ECO:0000269|PubMed:7769656" FT MUTAGEN 2207 FT /note="S->D: No effect on down-regulation of viral FT translation." FT /evidence="ECO:0000269|PubMed:31585734" FT MUTAGEN 2210 FT /note="S->A: No effect on NS5A hyperphosphorylation. FT Complete loss of NS5A-induced down-regulation of viral FT translation." FT /evidence="ECO:0000269|PubMed:31585734, FT ECO:0000269|PubMed:7769656" FT MUTAGEN 2210 FT /note="S->D: No effect on down-regulation of viral FT translation; increased NS5A dimerization." FT /evidence="ECO:0000269|PubMed:31585734" FT MUTAGEN 2221 FT /note="S->A: No effect on NS5A hyperphosphorylation." FT /evidence="ECO:0000269|PubMed:7769656" FT MUTAGEN 2448 FT /note="S->A: Partial loss of RNA-directed RNA polymerase FT phosphorylation. 60% loss of viral RNA replication." FT /evidence="ECO:0000269|PubMed:25031343" FT MUTAGEN 2461 FT /note="S->A: Partial loss of RNA-directed RNA polymerase FT phosphorylation. 30% loss of viral RNA replication." FT /evidence="ECO:0000269|PubMed:25031343" FT HELIX 786..801 FT /evidence="ECO:0007829|PDB:2K8J" FT STRAND 1030..1035 FT /evidence="ECO:0007829|PDB:3P8N" FT HELIX 1039..1048 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1057..1063 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1068..1074 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1077..1080 FT /evidence="ECO:0007829|PDB:3P8N" FT HELIX 1082..1085 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1090..1092 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1095..1097 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1100..1103 FT /evidence="ECO:0007829|PDB:3P8N" FT TURN 1104..1107 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1108..1112 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1128..1133 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1139..1144 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1146..1157 FT /evidence="ECO:0007829|PDB:3P8N" FT HELIX 1158..1161 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1168..1170 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1176..1186 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1189..1197 FT /evidence="ECO:0007829|PDB:3P8N" FT HELIX 1198..1206 FT /evidence="ECO:0007829|PDB:3P8N" FT STRAND 1680..1689 FT /evidence="ECO:0007829|PDB:3P8N" SQ SEQUENCE 3010 AA; 327021 MW; AA993794F46DB185 CRC64; MSTNPKPQRK TKRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRATR KTSERSQPRG RRQPIPKARR PEGRTWAQPG YPWPLYGNEG MGWAGWLLSP RGSRPSWGPT DPRRRSRNLG KVIDTLTCGF ADLMGYIPLV GAPLGGAARA LAHGVRVLED GVNYATGNLP GCSFSIFLLA LLSCLTIPAS AYEVRNVSGI YHVTNDCSNS SIVYEAADMI MHTPGCVPCV RESNFSRCWV ALTPTLAARN SSIPTTTIRR HVDLLVGAAA LCSAMYVGDL CGSVFLVSQL FTFSPRRYET VQDCNCSIYP GHVSGHRMAW DMMMNWSPTT ALVVSQLLRI PQAVVDMVAG AHWGVLAGLA YYSMVGNWAK VLIVMLLFAG VDGHTHVTGG RVASSTQSLV SWLSQGPSQK IQLVNTNGSW HINRTALNCN DSLQTGFIAA LFYAHRFNAS GCPERMASCR PIDEFAQGWG PITHDMPESS DQRPYCWHYA PRPCGIVPAS QVCGPVYCFT PSPVVVGTTD RFGAPTYSWG ENETDVLLLS NTRPPQGNWF GCTWMNSTGF TKTCGGPPCN IGGVGNNTLV CPTDCFRKHP EATYTKCGSG PWLTPRCMVD YPYRLWHYPC TVNFTVFKVR MYVGGVEHRL NAACNWTRGE RCDLEDRDRS ELSPLLLSTT EWQILPCSFT TLPALSTGLI HLHRNIVDVQ YLYGIGSAVV SFAIKWEYIL LLFLLLADAR VCACLWMMLL IAQAEATLEN LVVLNAASVA GAHGLLSFLV FFCAAWYIKG RLVPGAAYAL YGVWPLLLLL LALPPRAYAM DREMAASCGG AVFVGLVLLT LSPYYKVFLA RLIWWLQYFI TRAEAHLQVW VPPLNVRGGR DAIILLTCAV HPELIFDITK LLLAILGPLM VLQAGITRVP YFVRAQGLIR ACMLVRKVAG GHYVQMAFMK LAALTGTYVY DHLTPLRDWA HAGLRDLAVA VEPVVFSDME TKLITWGADT AACGDIISGL PVSARRGKEI LLGPADSFGE QGWRLLAPIT AYSQQTRGLL GCIITSLTGR DKNQVDGEVQ VLSTATQSFL ATCVNGVCWT VYHGAGSKTL AGPKGPITQM YTNVDQDLVG WPAPPGARSM TPCTCGSSDL YLVTRHADVV PVRRRGDSRG SLLSPRPISY LKGSSGGPLL CPSGHVVGIF RAAVCTRGVA KAVDFIPVES METTMRSPVF TDNSSPPAVP QTFQVAHLHA PTGSGKSTKV PAAYAAQGYK VLVLNPSVAA TLGFGAYMSK AHGIEPNIRT GVRTITTGGP ITYSTYCKFL ADGGCSGGAY DIIICDECHS TDSTTILGIG TVLDQAETAG ARLVVLATAT PPGSITVPHP NIEEVALSNT GEIPFYGKAI PIEAIKGGRH LIFCHSKKKC DELAAKLTGL GLNAVAYYRG LDVSVIPTSG DVVVVATDAL MTGFTGDFDS VIDCNTCVTQ TVDFSLDPTF TIETTTLPQD AVSRAQRRGR TGRGRSGIYR FVTPGERPSG MFDSSVLCEC YDAGCAWYEL TPAETSVRLR AYLNTPGLPV CQDHLEFWES VFTGLTHIDA HFLSQTKQAG DNLPYLVAYQ ATVCARAQAP PPSWDQMWKC LIRLKPTLHG PTPLLYRLGA VQNEVTLTHP ITKYIMACMS ADLEVVTSTW VLVGGVLAAL AAYCLTTGSV VIVGRIILSG RPAVIPDREV LYQEFDEMEE CASHLPYIEQ GMQLAEQFKQ KALGLLQTAT KQAEAAAPVV ESKWRALEVF WAKHMWNFIS GIQYLAGLST LPGNPAIASL MAFTASITSP LTTQNTLLFN ILGGWVAAQL APPSAASAFV GAGIAGAAVG SIGLGKVLVD ILAGYGAGVA GALVAFKVMS GEMPSTEDLV NLLPAILSPG ALVVGVVCAA ILRRHVGPGE GAVQWMNRLI AFASRGNHVS PTHYVPESDA AARVTQILSS LTITQLLKRL HQWINEDCST PCSGSWLKDV WDWICTVLSD FKTWLQSKLL PRLPGLPFLS CQRGYKGVWR GDGIMQTTCP CGAQITGHVK NGSMRIVGPK TCSNTWHGTF PINAYTTGPC TPSPAPNYSR ALWRVAAEEY VEVTRVGDFH YVTGMTTDNV KCPCQVPAPE FFTEVDGVRL HRYAPVCKPL LREEVVFQVG LNQYLVGSQL PCEPEPDVAV LTSMLTDPSH ITAETAKRRL ARGSPPSLAS SSASQLSAPS LKATCTTHHD SPDADLIEAN LLWRQEMGGN ITRVESENKV VILDSFDPIR AVEDEREISV PAEILRKPRK FPPALPIWAR PDYNPPLLES WKDPDYVPPV VHGCPLPSTK APPIPPPRRK RTVVLTESTV SSALAELATK TFGSSGSSAV DSGTATGPPD QASDDGDKGS DVESYSSMPP LEGEPGDPDL SDGSWSTVSG EAGEDVVCCS MSYTWTGALI TPCAAEESKL PINPLSNSLL RHHSMVYSTT SRSASLRQKK VTFDRLQVLD DHYRDVLKEM KAKASTVKAR LLSIEEACKL TPPHSAKSKF GYGAKDVRSL SSRAVNHIRS VWEDLLEDTE TPIDTTIMAK NEVFCVQPEK GGRKPARLIV FPDLGVRVCE KMALYDVVST LPQAVMGPSY GFQYSPGQRV EFLVNTWKSK KCPMGFSYDT RCFDSTVTEN DIRTEESIYQ CCDLAPEARQ AIRSLTERLY VGGPLTNSKG QNCGYRRCRA SGVLTTSCGN TLTCYLKATA ACRAAKLQDC TMLVNGDDLV VICESAGTQE DAAALRAFTE AMTRYSAPPG DPPQPEYDLE LITSCSSNVS VAHDASGKRV YYLTRDPTTP LARAAWETVR HTPVNSWLGN IIMYAPTLWA RMILMTHFFS ILLAQEQLEK ALDCQIYGAC YSIEPLDLPQ IIERLHGLSA FSLHSYSPGE INRVASCLRK LGVPPLRVWR HRARSVRAKL LSQGGRAATC GKYLFNWAVK TKLKLTPIPA ASQLDLSGWF VAGYNGGDIY HSLSRARPRW FMLCLLLLSV GVGIYLLPNR //