Protein: Genome polyprotein [Cleaved into: Core protein precursor (Capsid protein C) (p23); Mature core protein (p21); Envelope glycoprotein E1 (gp32) (gp35); Envelope glycoprotein E2 (NS1) (gp68) (gp70); Viroporin p7; Protease NS2 (p23) (EC 3.4.22.-) (Non-structural protein 2) (NS2); Serine protease/helicase NS3 (EC 3.4.21.98) (EC 3.6.1.15) (EC 3.6.4.13) (Hepacivirin) (NS3 helicase) (NS3 protease) (NS3P) (Viroporin p70); Non-structural protein 4A (NS4A) (p8); Non-structural protein 4B (NS4B) (p27); Non-structural protein 5A (NS5A) (p56/58); RNA-directed RNA polymerase (EC 2.7.7.48) (NS5B) (p68)] (P26664)
Organism: Hepatitis C virus genotype 1a (isolate 1) (HCV)
Function: Packages viral RNA to form a viral nucleocapsid, and promotes virion budding (Probable). Participates in the viral particle production as a result of its interaction with the non-structural protein 5A (By similarity). Binds RNA and may function as a RNA chaperone to induce the RNA structural rearrangements taking place during virus replication (By similarity). Modulates viral translation initiation by interacting with viral IRES and 40S ribosomal subunit (By similarity). Affects various cell signaling pathways, host immunity and lipid metabolism (Probable). Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by blocking the formation of phosphorylated STAT1 and promoting ubiquitin-mediated proteasome-dependent degradation of STAT1 (By similarity). Activates STAT3 leading to cellular transformation (By similarity). Regulates the activity of cellular genes, including c-myc and c-fos. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses TNF-induced NF-kappa-B activation, and activates AP-1. Binds to dendritic cells (DCs) via C1QR1, resulting in down-regulation of T-lymphocytes proliferation (By similarity). Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage (By similarity). Induces up-regulation of FAS promoter activity, and thereby contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity).
Subcellular location: [Core protein precursor]: Host endoplasmic reticulum membrane {ECO:0000269|PubMed:7491770}; Single-pass membrane protein {ECO:0000255}. Host mitochondrion membrane {ECO:0000269|PubMed:15254168}; Single-pass type I membrane protein {ECO:0000255}. Note=The C-terminal transmembrane domain of the core protein precursor contains an ER signal leading the nascent polyprotein to the ER membrane.; SUBCELLULAR LOCATION: [Mature core protein]: Virion {ECO:0000250|UniProtKB:Q99IB8}. Host cytoplasm {ECO:0000250|UniProtKB:Q99IB8}. Host nucleus {ECO:0000250|UniProtKB:P26662}. Host lipid droplet {ECO:0000250|UniProtKB:Q99IB8}. Note=Only a minor proportion of core protein is present in the nucleus (By similarity). Probably present on the surface of lipid droplets (By similarity). {ECO:0000250|UniProtKB:P27958}.; SUBCELLULAR LOCATION: [Envelope glycoprotein E1]: Virion membrane {ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host endoplasmic reticulum membrane; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P27958}. Note=The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase (By similarity). After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (By similarity). A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain (By similarity). These events explain the final topology of the protein (By similarity). {ECO:0000250|UniProtKB:P27958}.; SUBCELLULAR LOCATION: [Envelope glycoprotein E2]: Virion membrane {ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host endoplasmic reticulum membrane; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P27958}. Host lipid droplet {ECO:0000250|UniProtKB:Q9WMX2}. Note=The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase (By similarity). After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (By similarity). A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain (By similarity). These events explain the final topology of the protein (By similarity). {ECO:0000250|UniProtKB:P27958}.; SUBCELLULAR LOCATION: [Viroporin p7]: Host endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q99IB8}; Multi-pass membrane protein {ECO:0000250|UniProtKB:Q99IB8}. Host mitochondrion {ECO:0000250|UniProtKB:P27958}. Host cell membrane {ECO:0000250|UniProtKB:Q99IB8}. Note=The C-terminus of p7 membrane domain acts as a signal sequence (By similarity). After cleavage by host signal peptidase, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (By similarity). ER retention of p7 is leaky and a small fraction reaches the plasma membrane (By similarity). {ECO:0000250|UniProtKB:P27958}.; SUBCELLULAR LOCATION: [Protease NS2]: Host endoplasmic reticulum membrane {ECO:0000269|PubMed:12082096}; Multi-pass membrane protein {ECO:0000269|PubMed:12082096}. Note=Probably present on the surface of lipid droplets. {ECO:0000250|UniProtKB:Q99IB8}.; SUBCELLULAR LOCATION: [Serine protease/helicase NS3]: Host endoplasmic reticulum membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. Note=NS3 is associated to the ER membrane through its binding to NS4A. {ECO:0000305}.; SUBCELLULAR LOCATION: [Non-structural protein 4A]: Host endoplasmic reticulum membrane {ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Note=Host membrane insertion occurs after processing by the NS3 protease. {ECO:0000305}.; SUBCELLULAR LOCATION: [Non-structural protein 4B]: Host endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P27958}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P27958}. Note=A reorientation of the N-terminus into the ER lumen occurs post-translationally. {ECO:0000250|UniProtKB:P27958}.; SUBCELLULAR LOCATION: [Non-structural protein 5A]: Host endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P26662}; Peripheral membrane protein {ECO:0000250|UniProtKB:P27958}. Host cytoplasm, host perinuclear region {ECO:0000250|UniProtKB:P26662}. Host mitochondrion {ECO:0000250|UniProtKB:P26662}. Host cytoplasm {ECO:0000250|UniProtKB:P27958}. Host nucleus {ECO:0000250|UniProtKB:P26662}. Host lipid droplet {ECO:0000250|UniProtKB:P26662}. Note=Host membrane insertion occurs after processing by the NS3 protease (By similarity). Localizes at the surface of lipid droplets (By similarity). {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P27958}.; SUBCELLULAR LOCATION: [RNA-directed RNA polymerase]: Host cytoplasm {ECO:0000250|UniProtKB:P27958}. Host endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P27958}; Single-pass type I membrane protein {ECO:0000305}. Note=Host membrane insertion occurs after processing by the NS3 protease. {ECO:0000250|UniProtKB:P27958}.
Sequence: MSTNPKPQKKNKRNTNRRPQDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRTWAQPGYPWPLYGNEGCGWAGWLLSPRGSRPSWGPTDPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAPLGGAARALAHGVRVLEDGVNYATGNLPGCSFSIFLLALLSCLTVPASAYQVRNSTGLYHVTNDCPNSSIVYEAADAILHTPGCVPCVREGNASRCWVAMTPTVATRDGKLPATQLRRHIDLLVGSATLCSALYVGDLCGSVFLVGQLFTFSPRRHWTTQGCNCSIYPGHITGHRMAWDMMMNWSPTTALVMAQLLRIPQAILDMIAGAHWGVLAGIAYFSMVGNWAKVLVVLLLFAGVDAETHVTGGSAGHTVSGFVSLLAPGAKQNVQLINTNGSWHLNSTALNCNDSLNTGWLAGLFYHHKFNSSGCPERLASCRPLTDFDQGWGPISYANGSGPDQRPYCWHYPPKPCGIVPAKSVCGPVYCFTPSPVVVGTTDRSGAPTYSWGENDTDVFVLNNTRPPLGNWFGCTWMNSTGFTKVCGAPPCVIGGAGNNTLHCPTDCFRKHPDATYSRCGSGPWITPRCLVDYPYRLWHYPCTINYTIFKIRMYVGGVEHRLEAACNWTRGERCDLEDRDRSELSPLLLTTTQWQVLPCSFTTLPALSTGLIHLHQNIVDVQYLYGVGSSIASWAIKWEYVVLLFLLLADARVCSCLWMMLLISQAEAALENLVILNAASLAGTHGLVSFLVFFCFAWYLKGKWVPGAVYTFYGMWPLLLLLLALPQRAYALDTEVAASCGGVVLVGLMALTLSPYYKRYISWCLWWLQYFLTRVEAQLHVWIPPLNVRGGRDAVILLMCAVHPTLVFDITKLLLAVFGPLWILQASLLKVPYFVRVQGLLRFCALARKMIGGHYVQMVIIKLGALTGTYVYNHLTPLRDWAHNGLRDLAVAVEPVVFSQMETKLITWGADTAACGDIINGLPVSARRGREILLGPADGMVSKGWRLLAPITAYAQQTRGLLGCIITSLTGRDKNQVEGEVQIVSTAAQTFLATCINGVCWTVYHGAGTRTIASPKGPVIQMYTNVDQDLVGWPAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKGSSGGPLLCPAGHAVGIFRAAVCTRGVAKAVDFIPVENLETTMRSPVFTDNSSPPVVPQSFQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSKAHGIDPNIRTGVRTITTGSPITYSTYGKFLADGGCSGGAYDIIICDECHSTDATSILGIGTVLDQAETAGARLVVLATATPPGSVTVPHPNIEEVALSTTGEIPFYGKAIPLEVIKGGRHLIFCHSKKKCDELAAKLVALGINAVAYYRGLDVSVIPTSGDVVVVATDALMTGYTGDFDSVIDCNTCVTQTVDFSLDPTFTIETITLPQDAVSRTQRRGRTGRGKPGIYRFVAPGERPSGMFDSSVLCECYDAGCAWYELTPAETTVRLRAYMNTPGLPVCQDHLEFWEGVFTGLTHIDAHFLSQTKQSGENLPYLVAYQATVCARAQAPPPSWDQMWKCLIRLKPTLHGPTPLLYRLGAVQNEITLTHPVTKYIMTCMSADLEVVTSTWVLVGGVLAALAAYCLSTGCVVIVGRVVLSGKPAIIPDREVLYREFDEMEECSQHLPYIEQGMMLAEQFKQKALGLLQTASRQAEVIAPAVQTNWQKLETFWAKHMWNFISGIQYLAGLSTLPGNPAIASLMAFTAAVTSPLTTSQTLLFNILGGWVAAQLAAPGAATAFVGAGLAGAAIGSVGLGKVLIDILAGYGAGVAGALVAFKIMSGEVPSTEDLVNLLPAILSPGALVVGVVCAAILRRHVGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVTAILSSLTVTQLLRRLHQWISSECTTPCSGSWLRDIWDWICEVLSDFKTWLKAKLMPQLPGIPFVSCQRGYKGVWRVDGIMHTRCHCGAEITGHVKNGTMRIVGPRTCRNMWSGTFPINAYTTGPCTPLPAPNYTFALWRVSAEEYVEIRQVGDFHYVTGMTTDNLKCPCQVPSPEFFTELDGVRLHRFAPPCKPLLREEVSFRVGLHEYPVGSQLPCEPEPDVAVLTSMLTDPSHITAEAAGRRLARGSPPSVASSSASQLSAPSLKATCTANHDSPDAELIEANLLWRQEMGGNITRVESENKVVILDSFDPLVAEEDEREISVPAEILRKSRRFAQALPVWARPDYNPPLVETWKKPDYEPPVVHGCPLPPPKSPPVPPPRKKRTVVLTESTLSTALAELATRSFGSSSTSGITGDNTTTSSEPAPSGCPPDSDAESYSSMPPLEGEPGDPDLSDGSWSTVSSEANAEDVVCCSMSYSWTGALVTPCAAEEQKLPINALSNSLLRHHNLVYSTTSRSACQRQKKVTFDRLQVLDSHYQDVLKEVKAAASKVKANLLSVEEACSLTPPHSAKSKFGYGAKDVRCHARKAVTHINSVWKDLLEDNVTPIDTTIMAKNEVFCVQPEKGGRKPARLIVFPDLGVRVCEKMALYDVVTKLPLAVMGSSYGFQYSPGQRVEFLVQAWKSKKTPMGFSYDTRCFDSTVTESDIRTEEAIYQCCDLDPQARVAIKSLTERLYVGGPLTNSRGENCGYRRCRASGVLTTSCGNTLTCYIKARAACRAAGLQDCTMLVCGDDLVVICESAGVQEDAASLRAFTEAMTRYSAPPGDPPQPEYDLELITSCSSNVSVAHDGAGKRVYYLTRDPTTPLARAAWETARHTPVNSWLGNIIMFAPTLWARMILMTHFFSVLIARDQLEQALDCEIYGACYSIEPLDLPPIIQRLHGLSAFSLHSYSPGEINRVAACLRKLGVPPLRAWRHRARSVRARLLARGGRAAICGKYLFNWAVRTKLKLTPIAAAGQLDLSGWFTAGYSGGDIYHSVSHARPRWIWFCLLLLAAGVGIYLLPNR
InterPro domains: - IPR002518: Hepatitis C virus, Non-structural protein NS2 (domain) [811-1026]
- IPR004109: Hepatitis C virus, NS3 protease (domain) [1027-1208]
- IPR002521: Hepatitis C virus, Core protein, C-terminal (domain) [116-190]
- IPR038170: NS5A domain 1a superfamily (homologous_superfamily) [2014-2074]
- IPR009003: Peptidase S1, PA clan (homologous_superfamily) [1027-1212]
- IPR001490: Hepatitis C virus, Non-structural protein NS4b (domain) [1728-1921]
- IPR002522: Hepatitis C virus, Core protein, N-terminal (domain) [2-115]
- IPR001650: Helicase, C-terminal domain-like (domain) [1361-1538]
- IPR002868: Hepatitis C virus, Non-structural 5a protein (domain) [1974-1996]
- IPR002531: Hepatitis C virus, Non-structural protein E2/NS1 (domain) [386-729]
- IPR013193: Hepatitis C virus non-structural 5a, 1B domain (domain) [2068-2168]
- IPR011492: Non-structural protein NS3-like, DEAD-box helicase, flavivirus (domain) [1294-1355]
- IPR027417: P-loop containing nucleoside triphosphate hydrolase (homologous_superfamily) [1206-1646]
- IPR014001: Helicase superfamily 1/2, ATP-binding domain (domain) [1216-1385]
- IPR002166: RNA dependent RNA polymerase, hepatitis C virus (family) [2423-2932]
- IPR000745: Hepatitis C virus, Non-structural protein NS4a (domain) [1658-1711]
- IPR007094: RNA-directed RNA polymerase, catalytic domain (domain) [2634-2752]
- IPR002519: Hepatitis C virus, Envelope glycoprotein E1 (domain) [193-382]
- IPR024350: Hepatitus C virus, Non-structural 5a protein, C-terminal (domain) [2179-2420]
- IPR013192: Hepatitis C virus, Non-structural 5a protein, domain 1a (domain) [2006-2067]
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0005515 (protein binding), GO:0008134 (transcription factor binding), GO:0048306 (calcium-dependent protein binding), GO:0140297 (DNA-binding transcription factor binding), GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), GO:0016922 (nuclear receptor binding), GO:0042974 (nuclear retinoic acid receptor binding), GO:0046965 (nuclear retinoid X receptor binding)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0044419 (biological process involved in interspecies interaction between organisms), GO:0048519 (negative regulation of biological process), GO:0016032 (viral process), GO:0009605 (response to external stimulus), GO:0023057 (negative regulation of signaling), GO:0044068 (modulation by symbiont of host cellular process), GO:0051240 (positive regulation of multicellular organismal process), GO:0051241 (negative regulation of multicellular organismal process), GO:0051239 (regulation of multicellular organismal process), GO:0009892 (negative regulation of metabolic process), GO:0002683 (negative regulation of immune system process), GO:0009607 (response to biotic stimulus), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0023051 (regulation of signaling), GO:0048523 (negative regulation of cellular process), GO:0051707 (response to other organism), GO:0019222 (regulation of metabolic process), GO:0002682 (regulation of immune system process), GO:0035821 (modulation of process of another organism), GO:0044403 (biological process involved in symbiotic interaction), GO:0009893 (positive regulation of metabolic process), GO:0065009 (regulation of molecular function), GO:0019048 (modulation by virus of host process), GO:0048585 (negative regulation of response to stimulus), GO:0048522 (positive regulation of cellular process), GO:0009968 (negative regulation of signal transduction), GO:0043207 (response to external biotic stimulus), GO:0052173 (response to defenses of other organism), GO:0080134 (regulation of response to stress), GO:0009966 (regulation of signal transduction), GO:0060255 (regulation of macromolecule metabolic process), GO:0032101 (regulation of response to external stimulus), GO:0051098 (regulation of binding), GO:0001817 (regulation of cytokine production), GO:0031348 (negative regulation of defense response), GO:0051701 (biological process involved in interaction with host), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0039657 (suppression by virus of host gene expression), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0001819 (positive regulation of cytokine production), GO:0019054 (modulation by virus of host cellular process), GO:0034122 (negative regulation of toll-like receptor signaling pathway), GO:0010648 (negative regulation of cell communication), GO:0044093 (positive regulation of molecular function), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0075136 (response to host), GO:0009891 (positive regulation of biosynthetic process), GO:0075528 (modulation by virus of host immune response), GO:0002831 (regulation of response to biotic stimulus), GO:0050776 (regulation of immune response), GO:0031325 (positive regulation of cellular metabolic process), GO:0010646 (regulation of cell communication), GO:0044003 (modulation by symbiont of host process), GO:0009889 (regulation of biosynthetic process), GO:0039532 (negative regulation of viral-induced cytoplasmic pattern recognition receptor signaling pathway), GO:0031323 (regulation of cellular metabolic process), GO:0001818 (negative regulation of cytokine production), GO:0039503 (suppression by virus of host innate immune response), GO:0080090 (regulation of primary metabolic process), GO:0002832 (negative regulation of response to biotic stimulus), GO:0045834 (positive regulation of lipid metabolic process), GO:0052026 (modulation by symbiont of host transcription), GO:0032102 (negative regulation of response to external stimulus), GO:0031347 (regulation of defense response), GO:0052200 (response to host defenses), GO:0050687 (negative regulation of defense response to virus), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0051246 (regulation of protein metabolic process), GO:0032675 (regulation of interleukin-6 production), GO:0019056 (modulation by virus of host transcription), GO:0052031 (modulation by symbiont of host defense response), GO:0010468 (regulation of gene expression), GO:0032479 (regulation of type I interferon production), GO:0090208 (positive regulation of triglyceride metabolic process), GO:0044414 (suppression of host defenses by symbiont), GO:0090207 (regulation of triglyceride metabolic process), GO:0032715 (negative regulation of interleukin-6 production), GO:0010629 (negative regulation of gene expression), GO:0045088 (regulation of innate immune response), GO:0046889 (positive regulation of lipid biosynthetic process), GO:0062207 (regulation of pattern recognition receptor signaling pathway), GO:0010628 (positive regulation of gene expression), GO:1902532 (negative regulation of intracellular signal transduction), GO:0046890 (regulation of lipid biosynthetic process), GO:0051099 (positive regulation of binding), GO:0034248 (regulation of amide metabolic process), GO:0032481 (positive regulation of type I interferon production), GO:0050688 (regulation of defense response to virus), GO:0031326 (regulation of cellular biosynthetic process), GO:0032480 (negative regulation of type I interferon production), GO:0051101 (regulation of DNA binding), GO:0019216 (regulation of lipid metabolic process), GO:0039656 (modulation by virus of host gene expression), GO:0019049 (mitigation of host antiviral defense response), GO:0031328 (positive regulation of cellular biosynthetic process), GO:1902531 (regulation of intracellular signal transduction), GO:0039531 (regulation of viral-induced cytoplasmic pattern recognition receptor signaling pathway), GO:2000112 (regulation of cellular macromolecule biosynthetic process), GO:0010866 (regulation of triglyceride biosynthetic process), GO:0010867 (positive regulation of triglyceride biosynthetic process), GO:0043409 (negative regulation of MAPK cascade), GO:0043408 (regulation of MAPK cascade), GO:0034143 (regulation of toll-like receptor 4 signaling pathway), GO:0032647 (regulation of interferon-alpha production), GO:0032648 (regulation of interferon-beta production), GO:0043388 (positive regulation of DNA binding), GO:0052170 (suppression by symbiont of host innate immune response), GO:0052572 (response to host immune response), GO:0030682 (mitigation of host defenses by symbiont), GO:0006417 (regulation of translation), GO:0032728 (positive regulation of interferon-beta production), GO:0034121 (regulation of toll-like receptor signaling pathway), GO:0010608 (post-transcriptional regulation of gene expression), GO:0070372 (regulation of ERK1 and ERK2 cascade), GO:0052553 (modulation by symbiont of host immune response), GO:0070373 (negative regulation of ERK1 and ERK2 cascade), GO:0052167 (modulation by symbiont of host innate immune response), GO:0052562 (suppression by symbiont of host immune response)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0018995 (host cellular component), GO:0033643 (host cell part), GO:0043657 (host cell), GO:0033646 (host intracellular part), GO:0043656 (host intracellular region), GO:0033655 (host cell cytoplasm part), GO:0033647 (host intracellular organelle), GO:0030430 (host cell cytoplasm), GO:0033648 (host intracellular membrane-bounded organelle), GO:0044165 (host cell endoplasmic reticulum), GO:0042025 (host cell nucleus)