| IED ID | IndEnz0002001846 |
| Enzyme Type ID | protease001846 |
| Protein Name |
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 |
| Gene Name | |
| Organism | Hepatitis C virus genotype 1b (strain HC-J4) (HCV) |
| Taxonomic Lineage | Viruses Riboviria Orthornavirae Kitrinoviricota Flasuviricetes Amarillovirales Flaviviridae Hepacivirus Hepacivirus C Hepatitis C virus genotype 1 Hepatitis C virus subtype 1b Hepatitis C virus genotype 1b (strain HC-J4) (HCV) |
| Enzyme Sequence | MSTNPKPQRKTKRNTNRRPQDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKASERSQPRGRRQPIPKARRPEGRAWAQPGYPWPLYGNEGLGWAGWLLSPRGSRPSWGPTDPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAPLGGAARALAHGVRVLEDGVNYATGNLPGCSFSIFLLALLSCLTIPASAYEVRNVSGIYHVTNDCSNSSIVYEAADVIMHTPGCVPCVREGNSSRCWVALTPTLAARNASVPTTTIRRHVDLLVGTAAFCSAMYVGDLCGSIFLVSQLFTFSPRRHETVQDCNCSIYPGHVSGHRMAWDMMMNWSPTTALVVSQLLRIPQAVVDMVAGAHWGVLAGLAYYSMVGNWAKVLIVALLFAGVDGETHTTGRVAGHTTSGFTSLFSSGASQKIQLVNTNGSWHINRTALNCNDSLQTGFFAALFYAHKFNSSGCPERMASCRPIDWFAQGWGPITYTKPNSSDQRPYCWHYAPRPCGVVPASQVCGPVYCFTPSPVVVGTTDRSGVPTYSWGENETDVMLLNNTRPPQGNWFGCTWMNSTGFTKTCGGPPCNIGGVGNRTLICPTDCFRKHPEATYTKCGSGPWLTPRCLVDYPYRLWHYPCTLNFSIFKVRMYVGGVEHRLNAACNWTRGERCNLEDRDRSELSPLLLSTTEWQILPCAFTTLPALSTGLIHLHQNIVDVQYLYGVGSAFVSFAIKWEYILLLFLLLADARVCACLWMMLLIAQAEAALENLVVLNAASVAGAHGILSFLVFFCAAWYIKGRLAPGAAYAFYGVWPLLLLLLALPPRAYALDREMAASCGGAVLVGLVFLTLSPYYKVFLTRLIWWLQYFITRAEAHMQVWVPPLNVRGGRDAIILLTCAVHPELIFDITKLLLAILGPLMVLQAGITRVPYFVRAQGLIRACMLVRKVAGGHYVQMAFMKLGALTGTYVYNHLTPLRDWAHAGLRDLAVAVEPVVFSAMETKVITWGADTAACGDIILGLPVSARRGKEIFLGPADSLEGQGWRLLAPITAYSQQTRGVLGCIITSLTGRDKNQVEGEVQVVSTATQSFLATCINGVCWTVYHGAGSKTLAGPKGPITQMYTNVDLDLVGWQAPPGARSMTPCSCGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPVSYLKGSSGGPLLCPSGHVVGVFRAAVCTRGVAKAVDFIPVESMETTMRSPVFTDNSSPPAVPQTFQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSKAHGIDPNIRTGVRTITTGGSITYSTYGKFLADGGCSGGAYDIIICDECHSTDSTTILGIGTVLDQAETAGARLVVLATATPPGSVTVPHPNIEEIGLSNNGEIPFYGKAIPIEAIKGGRHLIFCHSKKKCDELAAKLTGLGLNAVAYYRGLDVSVIPPIGDVVVVATDALMTGFTGDFDSVIDCNTCVTQTVDFSLDPTFTIETTTVPQDAVSRSQRRGRTGRGRSGIYRFVTPGERPSGMFDSSVLCECYDAGCAWYELTPAETSVRLRAYLNTPGLPVCQDHLEFWESVFTGLTHIDAHFLSQTKQAGDNFPYLVAYQATVCARAQAPPPSWDQMWKCLIRLKPTLHGPTPLLYRLGAVQNEVILTHPITKYIMACMSADLEVVTSTWVLVGGVLAALAAYCLTTGSVVIVGRIILSGKPAVVPDREVLYQEFDEMEECASQLPYIEQGMQLAEQFKQKALGLLQTATKQAEAAAPVVESKWRALETFWAKHMWNFISGIQYLAGLSTLPGNPAIASLMAFTASITSPLTTQNTLLFNILGGWVAAQLAPPSAASAFVGAGIAGAAVGSIGLGKVLVDILAGYGAGVAGALVAFKVMSGEVPSTEDLVNLLPAILSPGALVVGVVCAAILRRHVGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVTQILSSLTITQLLKRLHQWINEDCSTPCSGSWLRDVWDWICTVLTDFKTWLQSKLLPRLPGVPFLSCQRGYKGVWRGDGIMQTTCPCGAQIAGHVKNGSMRIVGPRTCSNTWHGTFPINAYTTGPCTPSPAPNYSRALWRVAAEEYVEVTRVGDFHYVTGMTTDNVKCPCQVPAPEFFTEVDGVRLHRYAPACKPLLREDVTFQVGLNQYLVGSQLPCEPEPDVTVLTSMLTDPSHITAETAKRRLARGSPPSLASSSASQLSAPSLKATCTTHHDSPDADLIEANLLWRQEMGGNITRVESENKVVILDSFEPLHAEGDEREISVAAEILRKSRKFPSALPIWARPDYNPPLLESWKDPDYVPPVVHGCPLPPTKAPPIPPPRRKRTVVLTESNVSSALAELATKTFGSSGSSAVDSGTATALPDLASDDGDKGSDVESYSSMPPLEGEPGDPDLSDGSWSTVSEEASEDVVCCSMSYTWTGALITPCAAEESKLPINPLSNSLLRHHNMVYATTSRSASLRQKKVTFDRLQVLDDHYRDVLKEMKAKASTVKAKLLSIEEACKLTPPHSAKSKFGYGAKDVRNLSSRAVNHIRSVWEDLLEDTETPIDTTIMAKSEVFCVQPEKGGRKPARLIVFPDLGVRVCEKMALYDVVSTLPQAVMGSSYGFQYSPKQRVEFLVNTWKSKKCPMGFSYDTRCFDSTVTESDIRVEESIYQCCDLAPEARQAIRSLTERLYIGGPLTNSKGQNCGYRRCRASGVLTTSCGNTLTCYLKATAACRAAKLQDCTMLVNGDDLVVICESAGTQEDAAALRAFTEAMTRYSAPPGDPPQPEYDLELITSCSSNVSVAHDASGKRVYYLTRDPTTPLARAAWETARHTPINSWLGNIIMYAPTLWARMILMTHFFSILLAQEQLEKALDCQIYGACYSIEPLDLPQIIERLHGLSAFTLHSYSPGEINRVASCLRKLGVPPLRTWRHRARSVRAKLLSQGGRAATCGRYLFNWAVRTKLKLTPIPAASQLDLSGWFVAGYSGGDIYHSLSRARPRWFPLCLLLLSVGVGIYLLPNR |
| Enzyme Length | 3010 |
| Uniprot Accession Number | O92972 |
| Absorption | |
| Active Site | ACT_SITE 952; /note="For protease NS2 activity; shared with dimeric partner"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"; ACT_SITE 972; /note="For protease NS2 activity; shared with dimeric partner"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"; ACT_SITE 993; /note="For protease NS2 activity; shared with dimeric partner"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01030"; ACT_SITE 1083; /note="Charge relay system; for serine protease NS3 activity"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"; ACT_SITE 1107; /note="Charge relay system; for serine protease NS3 activity"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01166"; ACT_SITE 1165; /note="Charge relay system; for serine protease NS3 activity"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, ECO:0000269|PubMed:17239391" |
| Activity Regulation | ACTIVITY REGULATION: Inhibited by the antiviral drug hexamethylene amiloride (By similarity). Inhibited by amantadine (PubMed:12560074). Inhibition by amantadine appears to be genotype-dependent (By similarity). Also inhibited by long-alkyl-chain iminosugar derivatives (By similarity). {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:12560074}.; ACTIVITY REGULATION: [RNA-directed RNA polymerase]: Activity is up-regulated by PRK2/PKN2-mediated phosphorylation. {ECO:0000250|UniProtKB:P27958}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: [Serine protease/helicase NS3]: Reaction=Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1'.; EC=3.4.21.98; Evidence={ECO:0000250|UniProtKB:P27958}; CATALYTIC ACTIVITY: [Serine protease/helicase NS3]: Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + H(+) + phosphate; Xref=Rhea:RHEA:23680, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, ChEBI:CHEBI:57930, ChEBI:CHEBI:61557; EC=3.6.1.15; Evidence={ECO:0000250|UniProtKB:P27958}; CATALYTIC ACTIVITY: [Serine protease/helicase NS3]: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13; Evidence={ECO:0000250|UniProtKB:P27958}; CATALYTIC ACTIVITY: [RNA-directed RNA polymerase]: Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate + RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA-COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395; EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539}; |
| DNA Binding | |
| EC Number | 3.4.22.-; 3.4.21.98; 3.6.1.15; 3.6.4.13; 2.7.7.48 |
| Enzyme Function | FUNCTION: [Mature core protein]: 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 (By similarity). May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm (By similarity). Represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation (By similarity). 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 (By similarity). 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). {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:P29846, ECO:0000250|UniProtKB:Q99IB8, ECO:0000305}.; FUNCTION: [Envelope glycoprotein E1]: Forms a heterodimer with envelope glycoprotein E2, which mediates virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane (By similarity). Fusion with the host cell is most likely mediated by both E1 and E2, through conformational rearrangements of the heterodimer required for fusion rather than a classical class II fusion mechanism (By similarity). E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP) (By similarity). APOE associated to the LVP allows the initial virus attachment to cell surface receptors such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SCARB1) (By similarity). The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81 (By similarity). E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway (By similarity). Diffusion of the complex E1-E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry (By similarity). {ECO:0000250|UniProtKB:P27958}.; FUNCTION: [Envelope glycoprotein E2]: Forms a heterodimer with envelope glycoprotein E1, which mediates virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane (By similarity). Fusion with the host cell is most likely mediated by both E1 and E2, through conformational rearrangements of the heterodimer required for fusion rather than a classical class II fusion mechanism (By similarity). The interaction between envelope glycoprotein E2 and host apolipoprotein E/APOE allows the proper assembly, maturation and infectivity of the viral particles (By similarity). This interaction is probably promoted via the up-regulation of cellular autophagy by the virus (By similarity). E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP) (By similarity). APOE associated to the LVP allows the initial virus attachment to cell surface receptors such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SCARB1) (By similarity). The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81 (By similarity). E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway (By similarity). Diffusion of the complex E1-E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry (By similarity). Inhibits host EIF2AK2/PKR activation, preventing the establishment of an antiviral state (By similarity). Viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses (By similarity). These interactions allow the capture of circulating HCV particles by these cells and subsequent transmission to permissive cells (By similarity). Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). {ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958}.; FUNCTION: [Viroporin p7]: Ion channel protein that acts as a viroporin and plays an essential role in the assembly, envelopment and secretion of viral particles (Probable). Regulates the host cell secretory pathway, which induces the intracellular retention of viral glycoproteins and favors assembly of viral particles (By similarity). Creates a pore in acidic organelles and releases Ca(2+) and H(+) in the cytoplasm of infected cells, leading to a productive viral infection (Probable). High levels of cytoplasmic Ca(2+) may trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication (Probable). This ionic imbalance induces the assembly of the inflammasome complex, which triggers the maturation of pro-IL-1beta into IL-1beta through the action of caspase-1 (By similarity). Targets also host mitochondria and induces mitochondrial depolarization (By similarity). In addition of its role as a viroporin, acts as a lipid raft adhesion factor (By similarity). {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8, ECO:0000305, ECO:0000305|PubMed:12560074}.; FUNCTION: [Protease NS2]: Cysteine protease required for the proteolytic auto-cleavage between the non-structural proteins NS2 and NS3 (PubMed:17239391). The N-terminus of NS3 is required for the function of NS2 protease (active region NS2-3) (PubMed:17239391). Promotes the initiation of viral particle assembly by mediating the interaction between structural and non-structural proteins (By similarity). {ECO:0000250|UniProtKB:P27958, ECO:0000269|PubMed:17239391}.; FUNCTION: [Serine protease/helicase NS3]: Displays three enzymatic activities: serine protease with a chymotrypsin-like fold, NTPase and RNA helicase (By similarity). NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B (By similarity). The NS3/NS4A complex prevents phosphorylation of host IRF3, thus preventing the establishment of dsRNA induced antiviral state (By similarity). The NS3/NS4A complex induces host amino acid transporter component SLC3A2, thus contributing to HCV propagation (By similarity). NS3 RNA helicase binds to RNA and unwinds both dsDNA and dsRNA in the 3' to 5' direction, and likely resolves RNA complicated stable secondary structures in the template strand (By similarity). Binds a single ATP and catalyzes the unzipping of a single base pair of dsRNA (By similarity). Inhibits host antiviral proteins TBK1 and IRF3 thereby preventing the establishment of an antiviral state (By similarity). Cleaves host MAVS/CARDIF thereby preventing the establishment of an antiviral state (By similarity). Cleaves host TICAM1/TRIF, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state (By similarity). {ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q9WMX2}.; FUNCTION: [Non-structural protein 4B]: Induces a specific membrane alteration that serves as a scaffold for the virus replication complex (By similarity). This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS4B self-interaction contributes to its function in membranous web formation (By similarity). Promotes host TRIF protein degradation in a CASP8-dependent manner thereby inhibiting host TLR3-mediated interferon signaling (By similarity). Disrupts the interaction between STING and TBK1 contributing to the inhibition of interferon signaling (By similarity). {ECO:0000250|UniProtKB:P27958}.; FUNCTION: [Non-structural protein 5A]: Phosphorylated protein that is indispensable for viral replication and assembly (By similarity). Both hypo- and hyperphosphorylated states are required for the viral life cycle (By similarity). The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). Involved in RNA-binding and especially in binding to the viral genome (By similarity). Zinc is essential for RNA-binding (By similarity). Participates in the viral particle production as a result of its interaction with the mature viral core protein (By similarity). Its interaction with host VAPB may target the viral replication complex to vesicles (By similarity). Down-regulates viral IRES translation initiation (By similarity). Mediates interferon resistance, presumably by interacting with and inhibiting host EIF2AK2/PKR (By similarity). Prevents BIN1-induced apoptosis (By similarity). Acts as a transcriptional activator of some host genes important for viral replication when localized in the nucleus (By similarity). Via the interaction with host PACSIN2, modulates lipid droplet formation in order to promote virion assembly (By similarity). Modulates TNFRSF21/DR6 signaling pathway for viral propagation (By similarity). {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8, ECO:0000250|UniProtKB:Q9WMX2}.; FUNCTION: [RNA-directed RNA polymerase]: RNA-dependent RNA polymerase that performs primer-template recognition and RNA synthesis during viral replication. {ECO:0000250|UniProtKB:P27958}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 1230..1237; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00541 |
| Features | Active site (6); Beta strand (40); Chain (12); Compositional bias (2); Cross-link (1); Disulfide bond (9); Domain (4); Glycosylation (16); Helix (54); Initiator methionine (1); Intramembrane (1); Lipidation (3); Metal binding (13); Modified residue (12); Motif (7); Mutagenesis (7); Natural variant (31); Nucleotide binding (1); Propeptide (1); Region (27); Site (10); Topological domain (15); Transmembrane (14); Turn (9) |
| Keywords | 3D-structure;ATP-binding;Acetylation;Activation of host autophagy by virus;Apoptosis;Capsid protein;Clathrin-mediated endocytosis of virus by host;Disulfide bond;Fusion of virus membrane with host endosomal membrane;Fusion of virus membrane with host membrane;G1/S host cell cycle checkpoint dysregulation by virus;Glycoprotein;Helicase;Host cell membrane;Host cytoplasm;Host endoplasmic reticulum;Host lipid droplet;Host membrane;Host mitochondrion;Host nucleus;Host-virus interaction;Hydrolase;Inhibition of host MAVS by virus;Inhibition of host RLR pathway by virus;Inhibition of host STAT1 by virus;Inhibition of host TRAFs by virus;Inhibition of host innate immune response by virus;Inhibition of host interferon signaling pathway by virus;Interferon antiviral system evasion;Ion channel;Ion transport;Isopeptide bond;Lipoprotein;Magnesium;Membrane;Metal-binding;Modulation of host cell cycle by virus;Multifunctional enzyme;Nucleotide-binding;Nucleotidyltransferase;Oncogene;Palmitate;Phosphoprotein;Protease;RNA-binding;RNA-directed RNA polymerase;Ribonucleoprotein;SH3-binding;Serine protease;Thiol protease;Transcription;Transcription regulation;Transferase;Transmembrane;Transmembrane helix;Transport;Ubl conjugation;Viral RNA replication;Viral attachment to host cell;Viral envelope protein;Viral immunoevasion;Viral ion channel;Viral nucleoprotein;Viral penetration into host cytoplasm;Virion;Virus endocytosis by host;Virus entry into host cell;Zinc |
| Interact With | P06241; P62993; P08631; P06240; P07948; P84022; P62258; P19525; O92972; Q16513 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: [Core protein precursor]: Host endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P26664}; Single-pass membrane protein {ECO:0000255}. Host mitochondrion membrane {ECO:0000250|UniProtKB:P26664}; 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:P27958}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P27958}. Host mitochondrion {ECO:0000250|UniProtKB:P27958}. Host cell membrane {ECO:0000250|UniProtKB:P27958}. 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:0000250|UniProtKB:P27958}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P27958}. Host lipid droplet {ECO:0000250|UniProtKB:Q9WMX2}. Note=Probably present on the surface of lipid droplets. {ECO:0000250|UniProtKB:Q99IB8}.; SUBCELLULAR LOCATION: [Serine protease/helicase NS3]: Host endoplasmic reticulum membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}. 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.; 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:P27958}; Peripheral membrane protein {ECO:0000250|UniProtKB:P27958}. Host cytoplasm, host perinuclear region {ECO:0000250|UniProtKB:P27958}. Host mitochondrion {ECO:0000250|UniProtKB:P26662}. Host cytoplasm {ECO:0000250|UniProtKB:P27958}. Host nucleus {ECO:0000250|UniProtKB:P26662}. Host lipid droplet {ECO:0000250|UniProtKB:Q9WMX2}. 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; Single-pass type IV membrane protein {ECO:0000250|UniProtKB:P27958}. Note=Host membrane insertion occurs after processing by the NS3 protease. {ECO:0000250|UniProtKB:P27958}. |
| Modified Residue | MOD_RES 2; /note=N-acetylserine; by host; /evidence=ECO:0000250|UniProtKB:Q913V3; MOD_RES 53; /note=Phosphoserine; by host; /evidence=ECO:0000250|UniProtKB:Q01403; MOD_RES 99; /note=Phosphoserine; by host; /evidence=ECO:0000250|UniProtKB:Q01403; MOD_RES 116; /note=Phosphoserine; by host PKA; /evidence=ECO:0000250|UniProtKB:Q01403; MOD_RES 2194; /note=Phosphoserine; by host; in p56; /evidence=ECO:0000250|UniProtKB:Q9WMX2; MOD_RES 2197; /note=Phosphoserine; by host; in p58; /evidence=ECO:0000250|UniProtKB:Q9WMX2; MOD_RES 2201; /note=Phosphoserine; by host; in p58; /evidence=ECO:0000250|UniProtKB:Q9WMX2; MOD_RES 2204; /note=Phosphoserine; by host; in p58; /evidence=ECO:0000250|UniProtKB:Q9WMX2; MOD_RES 2207; /note=Phosphoserine; by host; in p58; /evidence=ECO:0000250|UniProtKB:Q99IB8; MOD_RES 2210; /note=Phosphoserine; by host; in p58; /evidence=ECO:0000250|UniProtKB:Q99IB8; MOD_RES 2448; /note=Phosphoserine; by host; /evidence=ECO:0000250|UniProtKB:P26662; MOD_RES 2461; /note=Phosphoserine; by host; /evidence=ECO:0000250|UniProtKB:P26662 |
| Post Translational Modification | PTM: [Genome polyprotein]: Specific enzymatic cleavages in vivo yield mature proteins (By similarity). The structural proteins, core, E1, E2 and p7 are produced by proteolytic processing by host signal peptidases (By similarity). The core protein precursor is synthesized as a 23 kDa, which is retained in the ER membrane through the hydrophobic signal peptide (By similarity). Cleavage by the signal peptidase releases the 21 kDa mature core protein (By similarity). The cleavage of the core protein precursor occurs between aminoacids 176 and 188 but the exact cleavage site is not known (By similarity). Some degraded forms of the core protein appear as well during the course of infection (By similarity). The other proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) are cleaved by the viral proteases (By similarity). Autoprocessing between NS2 and NS3 is mediated by the NS2 cysteine protease catalytic domain and regulated by the NS3 N-terminal domain (By similarity). {ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958}.; PTM: [Mature core protein]: Phosphorylated by host PKC and PKA. {ECO:0000250|UniProtKB:Q01403}.; PTM: [Mature core protein]: Ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation. {ECO:0000250|UniProtKB:Q03463}.; PTM: [Envelope glycoprotein E1]: Highly N-glycosylated. {ECO:0000250|UniProtKB:P27958}.; PTM: [Envelope glycoprotein E2]: Highly N-glycosylated. {ECO:0000250|UniProtKB:P27958}.; PTM: [Protease NS2]: Palmitoylation is required for NS2/3 autoprocessing and E2 recruitment to membranes. {ECO:0000250|UniProtKB:P27958}.; PTM: [Non-structural protein 4B]: Palmitoylated. This modification may play a role in its polymerization or in protein-protein interactions. {ECO:0000250|UniProtKB:P27958}.; PTM: [Non-structural protein 5A]: Phosphorylated on serines in a basal form termed p56 (By similarity). p58 is a hyperphosphorylated form of p56 (By similarity). p56 and p58 coexist in the cell in roughly equivalent amounts (By similarity). Hyperphosphorylation is dependent on the presence of NS4A (By similarity). Host CSNK1A1/CKI-alpha or RPS6KB1 kinases may be responsible for NS5A phosphorylation (By similarity). {ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P26664}.; PTM: [Non-structural protein 5A]: Tyrosine phosphorylation is essential for the interaction with host SRC. {ECO:0000250|UniProtKB:Q99IB8}.; PTM: [RNA-directed RNA polymerase]: The N-terminus is phosphorylated by host PRK2/PKN2. {ECO:0000250|UniProtKB:P26662}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); X-ray crystallography (57) |
| Cross Reference PDB | 1NB4; 1NB6; 1NB7; 2F55; 2MTS; 2XHU; 2XHV; 2XHW; 2YOJ; 3CSO; 3GNV; 3GNW; 3GOL; 3HKY; 3LKH; 3MWV; 3MWW; 3SKA; 3SKE; 3SKH; 3TYQ; 3TYV; 3U4O; 3U4R; 3UPH; 3UPI; 4DRU; 4EAW; 4GMC; 4IZ0; 4J02; 4J04; 4J06; 4J08; 4J0A; 4JJS; 4JJU; 4JTW; 4JTY; 4JTZ; 4JU1; 4JU2; 4JU3; 4JU4; 4JU6; 4JU7; 4JVQ; 4JY0; 4JY1; 4MZ4; 4OOW; 4RY4; 4RY5; 4RY6; 4RY7; 5CZB; 5NPH; 5NPI; |
| Mapped Pubmed ID | 14993658; 15784897; 16306038; 18852280; 19342234; 19507864; 20071590; 20219368; 20729191; 20942454; 21840715; 22104146; 22148957; 22220815; 22247956; 22473861; 23545108; 23768906; 23773186; 23841474; 24024973; 24176401; 24252545; 24900812; 25053847; 25428878; 27520942; 28512091; |
| Motif | MOTIF 5..13; /note=Nuclear localization signal; /evidence=ECO:0000250|UniProtKB:Q99IB8; MOTIF 38..43; /note=Nuclear localization signal; /evidence=ECO:0000250|UniProtKB:Q99IB8; MOTIF 58..64; /note=Nuclear localization signal; /evidence=ECO:0000250|UniProtKB:Q99IB8; MOTIF 66..71; /note=Nuclear localization signal; /evidence=ECO:0000250|UniProtKB:Q99IB8; MOTIF 1316..1319; /note=DECH box; /evidence=ECO:0000250|UniProtKB:Q99IB8; MOTIF 2322..2325; /note=SH3-binding; /evidence=ECO:0000255; MOTIF 2326..2334; /note=Nuclear localization signal; /evidence=ECO:0000250|UniProtKB:P26662 |
| Gene Encoded By | |
| Mass | 326,767 |
| Kinetics | |
| Metal Binding | METAL 1123; /note="Zinc 1; structural; required for NS3 protease activity and NS2/3 auto-cleavage activity"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, ECO:0000269|PubMed:17239391"; METAL 1125; /note="Zinc 1; structural; required for NS3 protease activity and NS2/3 auto-cleavage activity"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, ECO:0000269|PubMed:17239391"; METAL 1171; /note="Zinc 1; structural; required for NS3 protease activity and NS2/3 auto-cleavage activity"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, ECO:0000269|PubMed:17239391"; METAL 1175; /note="Zinc 1; structural; required for NS3 protease activity and NS2/3 auto-cleavage activity"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01166, ECO:0000269|PubMed:17239391"; METAL 1237; /note="Magnesium 1; catalytic; for NS3 helicase activity"; /evidence="ECO:0000250|UniProtKB:Q9WMX2"; METAL 1317; /note="Magnesium 1; catalytic; for NS3 helicase activity"; /evidence="ECO:0000250|UniProtKB:Q9WMX2"; METAL 2011; /note="Zinc 2; structural"; /evidence="ECO:0000250|UniProtKB:Q9WMX2"; METAL 2029; /note="Zinc 2; structural"; /evidence="ECO:0000250|UniProtKB:Q9WMX2"; METAL 2031; /note="Zinc 2; structural"; /evidence="ECO:0000250|UniProtKB:Q9WMX2"; METAL 2052; /note="Zinc 2; structural"; /evidence="ECO:0000250|UniProtKB:Q9WMX2"; METAL 2639; /note="Magnesium 2; catalytic; for RNA-directed RNA polymerase activity"; /evidence="ECO:0000250|UniProtKB:P26663"; METAL 2737; /note="Magnesium 2; catalytic; for RNA-directed RNA polymerase activity"; /evidence="ECO:0000250|UniProtKB:P26663"; METAL 2738; /note="Magnesium 2; catalytic; for RNA-directed RNA polymerase activity"; /evidence="ECO:0000250|UniProtKB:P26663" |
| Rhea ID | RHEA:23680; RHEA:13065; RHEA:21248 |
| Cross Reference Brenda | 2.7.7.48;3.4.21.98; |