ID Q9DTF0_9HEPC Unreviewed; 3010 AA. AC Q9DTF0; DT 01-MAR-2001, integrated into UniProtKB/TrEMBL. DT 01-MAR-2001, sequence version 1. DT 28-NOV-2006, entry version 28. DE Polyprotein. OS Hepatitis C virus. OC Viruses; ssRNA positive-strand viruses, no DNA stage; Flaviviridae; OC Hepacivirus. OX NCBI_TaxID=11103; RN [1] RP NUCLEOTIDE SEQUENCE. RC TISSUE=Serum; RX PubMed=11348851; DOI=10.1016/S1386-6346(00)00141-8; RA Takahashi K., Iwata K., Matsumoto M., Matsumoto H., Nakao K., RA Hatahara T., Ohta Y., Kanai K., Maruo H., Baba K., Hijikata M., RA Mishiro S.; RT "Hepatitis C virus (HCV) genotype 1b sequences from fifteen patients RT with hepatocellular carcinoma: the `progression score' revisited."; RL Hepatol. Res. 20:161-171(2001). RN [2] RP NUCLEOTIDE SEQUENCE. RX MEDLINE=92044457; PubMed=1658209; RA Oshima M., Tsuchiya M., Yagasaki M., Orita T., Hasegawa M., RA Tomonoh K., Kojima T., Hirata Y., Yamamoto O., Sho Y. et al.; RT "cDNA clones of Japanese hepatitis C virus genomes derived from a RT single patient show sequence heterogeneity."; RL J. Gen. Virol. 72:2805-2809(1991). CC -!- FUNCTION: Core protein packages viral RNA to form a viral CC nucleocapsid, and promotes virion budding. Modulates viral CC translation initiation by interacting with HCV IRES and 40S CC ribosomal subunit. Also regulates many host cellular functions CC such as signaling pathways and apoptosis. Prevents the CC establishment of cellular antiviral state by blocking the CC interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling CC pathways and by inducing human STAT1 degradation. Thought to play CC a role in virus-mediated cell transformation leading to CC hepatocellular carcinomas. Interacts with, and activates STAT3 CC leading to cellular transformation. May repress the promoter of CC p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the CC cytoplasm. Also represses cell cycle negative regulating factor CC CDKN1A, thereby interrupting an important check point of normal CC cell cycle regulation. Targets transcription factors involved in CC the regulation of inflammatory responses and in the immune CC response: suppresses NK-kappaB activation, and activates AP-1. CC Could mediate apoptotic pathways through association with TNF-type CC receptors TNFRSF1A and LTBR, although its effect on death CC receptor-induced apoptosis remains controversial. Enhances TRAIL CC mediated apoptosis, suggesting that it might play a role in CC immune-mediated liver cell injury. Seric core protein is able to CC bind C1QR1 at the T-cell surface, resulting in down-regulation of CC T-lymphocytes proliferation. May transactivate human MYC, Rous CC sarcoma virus LTR, and SV40 promoters. May suppress the human FOS CC and HIV-1 LTR activity. May alter lipid metabolism by interacting CC with hepatocellular proteins involved in lipid accumulation and CC storage (By similarity). CC -!- FUNCTION: Envelope glycoproteins E1 and E2 are involved in virus CC attachment to the host cell as well as in virus endocytosis and CC fusion with host membrane. E2 inhibits human EIF2AK2/PKR CC activation, preventing the establishment of an antiviral state. E2 CC is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are CC respectively found on dendritic cells (DCs), and on liver CC sinusoidal endothelial cells and macrophage-like cells of lymph CC node sinuses. These interactions allow capture of circulating HCV CC particles by these cells and subsequent transmission to permissive CC cells. DCs are professional antigen presenting cells, critical for CC host immunity by inducing specific immune responses against a CC broad variety of pathogens. They act as sentinels in various CC tissues where they entrap pathogens and convey them to local CC lymphoid tissue or lymph node for establishment of immunity. CC Capture of circulating HCV particles by these SIGN+ cells may CC facilitate virus infection of proximal hepatocytes and lymphocyte CC subpopulations and may be essential for the establishment of CC persistent infection (By similarity). CC -!- FUNCTION: NS3 displays three enzymatic activities: serine CC protease, NTPase and RNA helicase. NS3 serine protease, in CC association with NS4A, is responsible for the cleavages of NS3- CC NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also CC prevents phosphorylation of human IRF3, thus preventing the CC establishment of dsRNA induced antiviral state. NS3 RNA helicase CC binds to RNA and unwinds dsRNA in the 3' to 5' direction, and CC likely RNA stable secondary structure in the template strand (By CC similarity). CC -!- FUNCTION: NS4B induces a specific membrane alteration that serves CC as a scaffold for the virus replication complex. This membrane CC alteration gives rise to the so-called ER-derived membranous web CC that contains the replication complex (By similarity). CC -!- FUNCTION: NS5A is a component of the replication complex involved CC in RNA-binding. Down-regulates viral IRES translation initiation. CC Mediates interferon resistance, presumably by interacting with and CC inhibiting human EIF2AK2/PKR. The hyperphosphorylated form of NS5A CC is an inhibitor of viral replication (By similarity). CC -!- FUNCTION: NS5B is a RNA-dependent RNA polymerase that plays an CC essential role in the virus replication (By similarity). CC -!- FUNCTION: P7 seems to be a polymeric ion channel protein CC (viroporin) and is inhibited by the antiviral drug amantadine. CC Also inhibited by long-alkyl-chain iminosugar derivatives. CC Essential for infectivity (By similarity). CC -!- FUNCTION: Protease NS2-3 is a cysteine protease responsible for CC the autocatalytic cleavage of NS2-NS3. Seems to undergo self- CC inactivation following maturation (By similarity). CC -!- CATALYTIC ACTIVITY: Hydrolysis of four peptide bonds in the viral CC precursor polyprotein, commonly with Asp or Glu in the P6 CC position, Cys or Thr in P1 and Ser or Ala in P1'. CC -!- CATALYTIC ACTIVITY: N nucleoside triphosphate = N diphosphate + CC {RNA}(N). CC -!- CATALYTIC ACTIVITY: NTP + H(2)O = NDP + phosphate. CC -!- SUBUNIT: Core protein is a homomultimer that binds the C-terminal CC part of E1. Interacts with numerous cellular proteins. Interacts CC with human STAT1, inducing its degradation and human STAT3, CC constitutively activating it. Associates with human LTBR and CC TNFRSF1A receptors and possibly induces apoptosis. Binds to human CC SP110 isoform 3/Sp110b, HNRPK, C1QR1, YWHAE, DDX3X, APOA2 and RXRA CC proteins. Interacts with human CREB3 nuclear transcription CC protein, triggering cell transformation. May interact with human CC p53. Also binds human cytokeratins KRT8, KRT18, KRT19 and VIM CC (vimentin). E1 and E2 glycoproteins form a heterodimer that binds CC to human LDLR, CD81 and SCARB1 receptors, but this binding is not CC sufficient for infection, some additional liver specific cofactors CC may be needed. E2 binds and inhibits human EIF2AK2/PKR. Also binds CC human CD209/DC-SIGN and CLEC4M/DC-SIGNR. p7 forms a homopolymer. CC NS2 forms a homodimer and seems to interact with all other CC nonstructural (NS) proteins. NS4A interacts with NS3 serine CC protease and stabilizes its folding. NS3-NS4A complex is essential CC for the activation of the latter and allows membrane anchorage of CC NS3. NS3 interacts with TANK-binding kinase TBK1. NS4B and NS5A CC form homodimers and seem to interact with all other nonstructural CC (NS) proteins. NS5A also interacts with human EIF2AK2/PKR, GRB2, CC PIK3R1 and with most Src-family kinases. NS5B is a homooligomer CC (By similarity). CC -!- SUBCELLULAR LOCATION: The virion assembly and budding occurs from CC the endoplasmic reticulum (ER) membrane or ER-derived membranes. CC The C-terminal transmembrane domain of core protein contains an ER CC signal leading the nascent polyprotein to the ER membrane. The C- CC termini of E1, E2, and p7 membrane domains act as signal CC sequences. After cleavage by host signal peptidase, these membrane CC sequences retain at the C-terminus of the concerned proteins CC (core, E1, E2 and p7), serving as ER membrane anchors. Core CC protein is cytoplasmic. It is also located on mitochondrial and ER CC membranes, as well as at the surface of lipid droplets. A minor CC proportion is present in the nucleus. An unknown proportion is CC secreted. E1, E2, NS2 and NS4B are integral ER membrane proteins. CC The C-terminal transmembrane domains of envelope glycoproteins E1 CC and E2 form a hairpin structure before cleavage by host signal CC peptidase. A reorientation of the second hydrophobic stretch CC occurs after cleavage producing a single reoriented transmembrane CC domain. These events explain the final topology of these proteins. CC ER retention of E1 and E2 is leaky and, in overexpression CC conditions, a small fraction of both proteins reaches the plasma CC membrane. NS3 is associated to the ER membrane through its binding CC to NS4A. Membrane insertion of the membrane-anchored proteins CC NS4A, NS5A and NS5B occurs after processing by the NS3 protease. CC NS5A is perinuclear. A fraction of p7 localizes to the plasma CC membrane (By similarity). CC -!- DOMAIN: The N-terminal one-third of serine protease NS3 contains CC the protease activity. This region contains a zinc atom that does CC not belong to the active site, but may play a structural rather CC than a catalytic role. This region is essential for the activity CC of protease NS2-3, maybe by contributing to the folding of the CC latter. The helicase activity is located in the C-terminus of NS3 CC (By similarity). 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; AB049087; BAB18800.1; -; Genomic_RNA. DR PIR; A61196; A61196. DR PIR; PQ0246; PQ0246. DR PIR; PQ0251; PQ0251. DR PIR; PQ0252; PQ0252. DR PIR; PQ0254; PQ0254. DR PIR; PS0329; PS0329. DR HSSP; Q8JYS1; 1CWX. DR SMR; Q9DTF0; 902-1026, 1029-1657, 2008-2170, 2420-2949. DR euHCVdb; AB049087; -. DR GO; GO:0019028; C:viral capsid; IEA:InterPro. DR GO; GO:0019031; C:viral envelope; IEA:InterPro. DR GO; GO:0005524; F:ATP binding; IEA:InterPro. DR GO; GO:0004386; F:helicase activity; IEA:InterPro. DR GO; GO:0003723; F:RNA binding; IEA:InterPro. DR GO; GO:0003968; F:RNA-directed RNA polymerase activity; IEA:InterPro. DR GO; GO:0008236; F:serine-type peptidase activity; IEA:InterPro. DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro. DR GO; GO:0006508; P:proteolysis; IEA:InterPro. DR GO; GO:0006350; P:transcription; IEA:InterPro. DR GO; GO:0019087; P:transformation of host cell by virus; IEA:InterPro. DR GO; GO:0019079; P:viral genome replication; IEA:InterPro. DR InterPro; IPR014001; DEAD-like_N. DR InterPro; IPR002522; HCV_capsid. DR InterPro; IPR002521; HCV_core. DR InterPro; IPR002519; HCV_env. DR InterPro; IPR002531; HCV_NS1. DR InterPro; IPR000745; HCV_NS4a. DR InterPro; IPR001490; HCV_NS4b. DR InterPro; IPR002868; HCV_NS5a. DR InterPro; IPR013193; HCV_NS5a_1b. DR InterPro; IPR013192; HCV_NS5a_Zn_bd. DR InterPro; IPR002166; HCV_RdRP. DR InterPro; IPR014021; Helic_SF1/SF2_ATP_bd. DR InterPro; IPR001650; Helicase_C. DR InterPro; IPR002518; Pept_C18_HCV_NS2. DR InterPro; IPR009003; Pept_Ser_Cys. DR InterPro; IPR004109; Peptidase_S29. DR InterPro; IPR007094; RNA_pol_PSvir. 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; PF00271; Helicase_C; 1. DR Pfam; PF02907; Peptidase_S29; 1. DR Pfam; PF00998; RdRP_3; 1. DR SMART; SM00487; DEXDc; 1. DR PROSITE; PS51192; HELICASE_ATP_BIND_1; 1. DR PROSITE; PS51194; HELICASE_CTER; 1. DR PROSITE; PS50507; RDRP_SSRNA_POS; 1. KW ATP-binding; Capsid protein; Endoplasmic reticulum; Envelope protein; KW Helicase; Host-virus interaction; Hydrolase; KW Interferon antiviral system evasion; Membrane; Nucleotide-binding; KW Nucleotidyltransferase; Oncogene; Protease; RNA replication; KW RNA-binding; RNA-directed RNA polymerase; Ribonucleoprotein; KW Serine protease; Thiol protease; Transcription; KW Transcription regulation; Transferase; Transmembrane; KW Viral nucleoprotein; Virion protein; Zinc. SQ SEQUENCE 3010 AA; 327156 MW; 7A9C7B1273266FF3 CRC64; MSTNPKPQRK TKRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRATR KTSERSQPRG RRQPIPKARQ PEGRAWAQPG YPWPLYGNEG LGWAGWLLSP RGSRPSWGPT DPRRRSRNLG KVIDTLTCGF ADLMGYIPLV GGPLGGAARA LAHGVRVLED GVNYATGNLP GCSFSIFLLA LLSCLTIPAS AYEVRNVSGV YHVTNDCSNS SIVYEAADMI MHTPGCVPCV RENDCSRCWV ALTPTLAARN SSIPTTTIRR HVDLLVGAAA FCSAMYVGDL CGSIFLVSQL FTFSPRRYWT VQDCNCSIYP GHVSGHRMAW DMMMNWSPTT ALVVSQLLRI PQSVVDMVAG AHWGVLAGLA YYSMVGNWAK VLIVMLLFAG VDGVTHMTGG QVSHNTRSFM SLFTCGPSQK IQLINTNGSW HINRTALNCN DSLQTGFLAA LFYAHNLNSS GCPERMASCR SIDKFAQGWG PITHVVPDTW DQRPYCWHYA PKPCGIVPAS QVCGPVYCFT PSPVVVGTTD RFGVPTYTWG ENETDVLFLN NTRPPQGNWF GCTWMNSTGF TKTCGGPPCN IGGVGNNTLI CPTDCFRKHP EATYTKCGSG PWLTPRCMVD YPYRLWHYPC TVNFTIFKVR MYVGGVEHRL NAACNWTRGE RCDLEDRDRS ELSPLLLSTT EWQVLPCSFT PLPALSTGLI HLHQNIVDVQ YLYGIGSAVV SVVIKWEYVL LLFLLLADAR VCSCLWMMLL IAQAEAALEN LVVLNAASVA GAHGTLSFLV FFCAAWYIKG KLVPGAAYAL YGVWPLLLLL LALPHRAYAM DPEMAASCGG AVFVGLALLT LSPHYKAFLA RLIWWLQYFI TRAEAHLQVW IPPLNVRGGR DAIILLACAV HPELIFDITK ILLAILGPLM VLQAGLTRVP YFVRAQGLIR VCMLVRKVAG GHYFQMALMK LAALTGTYVY DHLTPLRDWA HVGLRDLAVA VEPVVFSDME TKIITWGADT AACGDIISGL PVSARRGREI LLGPADSFRE QGWRLLAPIT AYSQQTRGLL GCIITSLTGR DKNQVEGEVQ VVSTATQSFL ATCVNGVCWT VYHGAGSKTL AGPKGPITQM YTNVDQDLVG WQAPPGARSL TPCTCGSSDL YLVTRHADVI PVRRRGDSRG SLLSPRPVSY LKGSSGGPLL CPSGHAVGIF RAAVCTRGVA KAVDFIPVES METTMRSPVF TDNSSPPAVP QTFQVAHLHA PTGSGKSTKV PAAYAAQGYK VLVLNPSVAA TLSFGAYMSK AHGVDPNIRT GVRTITTGAP ITYSTYGKFL ADGGCSGGAY DIIICDECHS TDSTSILGIG TVLDQAETAG ARLVLLATAT PPGSVTVPHP NIEEVALSNT GEIPFYGKAI PIETIKGGRH LIFCHSKKKC DELAAKLSAL GVNAVAYYRG LDVSVIPTSG NVVVVATDAL MTGYTGDFDS VIDCNTCVTQ TVDFSLDPTF TIETTTVPQD AVSRSQRRGR TGRGRAGIYR FVTPGERPSG MFDSSVLCEC YDAGCAWYEL TPAETSVRLR AYLNTPGLPV CQDHLEFWES VFTGLTHIDA HFLSQTKQAG DNFPYLVAYQ ATVCARAQAP PPSWDQMWKC LIRLKPTLHG PTPLLYRLGA VQNEVTLTHP ITKFIMACMS ADLEVVTSTW VLVGGVLAAL AAYCLTTGSV VIVGRIILSG KPAVIPDREV LYREFDEMEE CASHLPYIEQ GMQLAEQFKQ KALGLLQTAT KQAEAAAPVV ESKWRALETF WAKHMWNFIS GIQYLAGLST LPGNPAIASL MAFTASITSP LTTQHTLLFN ILGGWVAAQL APPSAASAFV GAGIAGAAVG SIGLGKVLVD ILAGYGAGVA GALVAFKVMS GEMPSAEDMV NLLPAILSPG ALVVGVVCAA ILRRHVGPGE GAVQWMNRLI AFASRGNHVS PTHYVPESDA AARVTQILSS LTITQLLKRL HQWINEDCST PCSGSWLRDV WDWICTVLTD FKTWLQSKLL PRLPGVPFFS CQRGYKGVWL GDGVMQTTCP CGAQISGHVK NGSMKIVGPK TCSNTWHGTF PINAYTTGPC TPSPAPNYSR ALWRVAAEEY VEVTRVGEFH YVTGMTTDNV KCPCQVPSPE FFTEVDGVRL HRYAPACKPL LRDEVTFQVG LNQYPVGSQL PCEPEPDVAV LTSMLTDPSH ITAETARRRL ARGSPPSLAS SSASQLSAPS LKATCTTCHD SPDADLIEAN LLWRQEMGGN ITRVESENKV VILDSFDPLR AEEDEREVSV AAEILRKTRK FPPAIPIWAR PDYNPPLLES WKDPDYVPPV VHGCPLPPTK APPIPPPRRK RTVILTESTV SSALAELATK TFGSSGSSAV DSGTATAPPD QPSDDGDTGS DVGSYSSMPP LEGEPGDPDL SDGSWSTVSE EAGEDVVCCS MSYTWTGALI TPCGAEETKL PINALSNSLL RHHNMVYATT SRSASQRQRK VTFDRLQVLD DHYRDVLKEM KAKASTVKAK LLSVEEACKL TPPHSARSKF GYGAKDVRNL SSKAVNHIRS VWKDLLEDTE TPINTTIMAK SEVFCVQPEK GGRKPARLIV FPDLGVRVCE KMALYDVVST LPQAVMGSSY GFQYSPGQRV EFLVNAWKSK KSPMGFAYDT RCFDSTVTES DIRVEESIYQ CCDLAPEARQ VIRSLTERLY IGGPLTNSKG QNCGYRRCRA SGVLTTSCGN TLTCYLKASA ACRAAKLQDC TMLVCGDDLV VICESAGTQE DAANLRVFTE AMTRYSAPPG DPPRPEYDLE LITSCSSNVS VAHDAAGKRV YYLTRDPITP LARAAWETAR HTPVNSWLGN IIMYAPTLWA RMILMTHFFS ILLAQEQLEK ALDCQIYGAV YSIEPLDLPQ IIQRLHGLSA FSLHSYSPGE INRVASCLRK LGVPPLRVWR HRARSVRAKL LSQGGRAATC GKYLFNWAVR TKLKLTPIPA ASQLDLSGWF VAGYSGGDIY HSLSRARPRW FMWCLLLLSV GVGIYLLPNR //