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Details on Person UniProt:P27958 POLG
| Class:Id | ReferenceGeneProduct:9731837 |
|---|---|
| _chainChangeLog | initiator methionine: for 9731837 added on Mon Feb 26 2024;chain:2-3011 for 9731837 added on Mon Feb 26 2024;chain:2-191 for 9731837 added on Mon Feb 26 2024;chain:2-177 for 9731837 added on Mon Feb 26 2024;propeptide:178-191 for 9731837 added on Mon Feb 26 2024;chain:192-383 for 9731837 added on Mon Feb 26 2024;chain:384-746 for 9731837 added on Mon Feb 26 2024;chain:747-809 for 9731837 added on Mon Feb 26 2024;chain:810-1026 for 9731837 added on Mon Feb 26 2024;chain:1027-1657 for 9731837 added on Mon Feb 26 2024;chain:1658-1711 for 9731837 added on Mon Feb 26 2024;chain:1712-1972 for 9731837 added on Mon Feb 26 2024;chain:1973-2420 for 9731837 added on Mon Feb 26 2024;chain:2421-3011 for 9731837 added on Mon Feb 26 2024;initiator methionine: for 9731837 removed on Fri Aug 15 2025;initiator methionine:1 for 9731837 added on Fri Aug 15 2025 |
| _displayName | UniProt:P27958 POLG |
| _timestamp | 2025-08-15 21:40:28 |
| chain | initiator methionine:1 chain:2-3011 chain:2-191 chain:2-177 propeptide:178-191 chain:192-383 chain:384-746 chain:747-809 chain:810-1026 chain:1027-1657 chain:1658-1711 chain:1712-1972 chain:1973-2420 chain:2421-3011 |
| checksum | 772CBB29CCD94753 |
| comment | 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 (PubMed:18033802). 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) (PubMed:23799612). 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 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 (PubMed:11086025, PubMed:17881511). Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage (PubMed:14602201). Induces up-regulation of FAS promoter activity, and thereby contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (PubMed:14602201).FUNCTION 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 (PubMed:14990718, PubMed:16894197). 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 (PubMed:16533059, PubMed:24698129, PubMed:29505618). E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP) (PubMed:24838241, PubMed:25122793, PubMed:29695434). 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) (PubMed:12356718, PubMed:12913001, PubMed:12970454, PubMed:22767607, PubMed:28404852). The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81 (PubMed:12913001, PubMed:22767607). E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway (PubMed:22855500). 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) (PubMed:12913001, PubMed:12970454, PubMed:19182773, PubMed:20375010, PubMed:24038151).FUNCTION 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 (PubMed:14990718, PubMed:16894197). 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 (PubMed:16533059, PubMed:24698129, PubMed:29505618). The interaction between E2 and host apolipoprotein E/APOE allows the proper assembly, maturation and infectivity of the viral particles (PubMed:25122793, PubMed:29695434). This interaction is probably promoted via the up-regulation of cellular autophagy by the virus (PubMed:29695434). E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP) (PubMed:24838241, PubMed:25122793, PubMed:29695434). 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) (PubMed:12356718, PubMed:12913001, PubMed:12970454, PubMed:22767607, PubMed:28404852). The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81 (PubMed:12913001, PubMed:22767607). E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway (By similarity) (PubMed:12913001, PubMed:12970454, PubMed:19182773, PubMed:20375010, PubMed:22855500, PubMed:24038151). 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) (PubMed:12913001, PubMed:12970454, PubMed:19182773, PubMed:20375010, PubMed:24038151). 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 DCs, and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses (PubMed:15371595). These interactions allow the capture of circulating HCV particles by these cells and subsequent facilitated transmission to permissive cells such as hepatocytes and lymphocyte subpopulations (PubMed:15371595). The interaction between E2 and host amino acid transporter complex formed by SLC3A2 and SLC7A5/LAT1 may facilitate viral entry into host cell (PubMed:30341327).FUNCTION Ion channel protein that acts as a viroporin and plays an essential role in the assembly, envelopment and secretion of viral particles (PubMed:12719519, PubMed:20824094, PubMed:27320856). Participates in virus envelopment by coordinating the encounter between NS5A and NS2-based assembly sites loaded with E1/E2 heterodimer, which subsequently leads to nucleocapsid envelopment (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) (PubMed:20824094). 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). The release of Ca(2+) may also activate the inflamasome leading to chronic inflammation (Probable) (PubMed:31801866). Targets also host mitochondria and induces mitochondrial depolarization (PubMed:29039530). In addition of its role as a viroporin, acts as a lipid raft adhesion factor (PubMed:27320856).FUNCTION Cysteine protease required for the proteolytic auto-cleavage between the non-structural proteins NS2 and NS3 (PubMed:8248148). The N-terminus of NS3 is required for the function of NS2 protease (active region NS2-3) (By similarity). Promotes the initiation of viral particle assembly by mediating the interaction between structural and non-structural proteins (PubMed:21147927).FUNCTION Displays three enzymatic activities: serine protease with a chymotrypsin-like fold, NTPase and RNA helicase (PubMed:25551442). NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B (PubMed:8035505, PubMed:8189513, PubMed:8386278). 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 (PubMed:30341327). 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 (Probable). Binds a single ATP and catalyzes the unzipping of a single base pair of dsRNA (PubMed:21940894). 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 (PubMed:16177806, PubMed:16301520). Cleaves host TICAM1/TRIF, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state (PubMed:15710891).FUNCTION Peptide cofactor which forms a non-covalent complex with the N-terminal of NS3 serine protease (PubMed:21507982, PubMed:8189513). 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 (PubMed:30341327).FUNCTION Induces a specific membrane alteration that serves as a scaffold for the virus replication complex (PubMed:12021330). This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (PubMed:12021330). NS4B self-interaction contributes to its function in membranous web formation (PubMed:16731940). Promotes host TRIF protein degradation in a CASP8-dependent manner thereby inhibiting host TLR3-mediated interferon signaling (PubMed:29782532). Disrupts the interaction between STING and TBK1 contributing to the inhibition of interferon signaling (PubMed:23542348).FUNCTION Phosphorylated protein that is indispensable for viral replication and assembly (PubMed:27578425). 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 (Probable). Zinc is essential for RNA-binding (PubMed:20926572). Participates in the viral particle production as a result of its interaction with the viral mature 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 (PubMed:16951545). Prevents BIN1-induced apoptosis (PubMed:16530520). 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 (PubMed:31801866). Modulates TNFRSF21/DR6 signaling pathway for viral propagation (PubMed:28743875).FUNCTION RNA-dependent RNA polymerase that performs primer-template recognition and RNA synthesis during viral replication (PubMed:20729191). Initiates RNA transcription/replication at a flavin adenine dinucleotide (FAD), resulting in a 5'- FAD cap on viral RNAs. In this way, recognition of viral 5' RNA by host pattern recognition receptors can be bypassed (PubMed:37407817), thereby evading activation of antiviral pathways.CATALYTIC ACTIVITY 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'.CATALYTIC ACTIVITY a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H(+)CATALYTIC ACTIVITY ATP + H2O = ADP + phosphate + H(+)CATALYTIC ACTIVITY RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphateCOFACTOR Activity of protease NS2 is dependent on zinc ions and completely inhibited by EDTA. This is probably due to the fact that NS2 protease activity needs NS3 N-terminus that binds a zinc atom (active region NS2-3).COFACTOR Binds 1 zinc ion, which has a structural role (By similarity). The magnesium ion is essential for the helicase activity (By similarity).COFACTOR Binds 2 magnesium ion that constitute a dinuclear catalytic metal center.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 (PubMed:12719519).ACTIVITY REGULATION Activity is up-regulated by PRK2/PKN2-mediated phosphorylation.SUBUNIT Homooligomer (PubMed:25351725). Interacts with E1 (via C-terminus) (PubMed:8764026). Interacts with the non-structural protein 5A (By similarity). Interacts (via N-terminus) with host STAT1 (via SH2 domain); this interaction results in decreased STAT1 phosphorylation and ubiquitin-mediated proteasome-dependent STAT1 degradation, leading to decreased IFN-stimulated gene transcription (PubMed:23799612). Interacts with host STAT3; this interaction constitutively activates STAT3 (By similarity). Associates with host LTBR receptor (By similarity). Interacts with host TNFRSF1A receptor and possibly induces apoptosis (By similarity). Interacts with host HNRPK (By similarity). Interacts with host YWHAE (By similarity). Interacts with host UBE3A/E6AP (By similarity). Interacts with host DDX3X (By similarity). Interacts with host APOA2 (By similarity). Interacts with host RXRA protein (By similarity). Interacts with host SP110 isoform 3/Sp110b; this interaction sequesters the transcriptional corepressor SP110 away from the nucleus (By similarity). Interacts with host CREB3 nuclear transcription protein; this interaction triggers cell transformation (By similarity). Interacts with host ACY3 (PubMed:19486448). Interacts with host C1QR1 (PubMed:11086025). Interacts with host RBM24; this interaction, which enhances the interaction of the mature core protein with 5'-UTR, may inhibit viral translation and favor replication (By similarity). Interacts (via N-terminus) with host EIF2AK2/PKR (via N-terminus); this interaction induces the autophosphorylation of EIF2AK2 (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).SUBUNIT Forms a heterodimer with envelope glycoprotein E2 (PubMed:11145889, PubMed:14990718, PubMed:24038151). Interacts with mature core protein (PubMed:8764026). Interacts with protease NS2 (PubMed:21147927). The heterodimer E1/E2 interacts with host CLDN1; this interaction plays a role in viral entry into host cell (PubMed:24038151). Interacts with host SPSB2 (via C-terminus) (PubMed:31344133). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Interacts with host NEURL3; this interaction prevents E1 binding to glycoprotein E2 (PubMed:30111563).SUBUNIT Forms a heterodimer with envelope glycoprotein E1 (PubMed:11145889, PubMed:14990718, PubMed:24038151). Interacts with host CD81 and SCARB1 receptors; these interactions play a role in viral entry into host cell (PubMed:12356718, PubMed:12913001, PubMed:12970454). Interacts with host EIF2AK2/PKR; this interaction inhibits EIF2AK2 and probably allows the virus to evade the innate immune response (PubMed:10390359). Interacts with host CD209/DC-SIGN and CLEC4M/DC-SIGNR (PubMed:15371595). Interact with host SPCS1; this interaction is essential for viral particle assembly (By similarity). Interacts with protease NS2 (PubMed:21147927). The heterodimer E1/E2 interacts with host CLDN1; this interaction plays a role in viral entry into host cell (PubMed:24038151). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Interacts with host SLC3A2/4F2hc; the interaction may facilitate viral entry into host cell (PubMed:30341327). Interacts with human PLSCR1 (By similarity).SUBUNIT Homohexamer (PubMed:12560074). Homoheptamer (By similarity). Interacts with protease NS2 (By similarity).SUBUNIT Homodimer (PubMed:16862121). Interacts with host SPCS1; this interaction is essential for viral particle assembly (By similarity). Interacts with envelope glycoprotein E1 (PubMed:21147927). Interacts with envelope glycoprotein E2 (PubMed:21147927). Interacts with viroporin p7 (By similarity). Interacts with serine protease/helicase NS3 (PubMed:21147927). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12692242, PubMed:12692249). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).SUBUNIT Interacts with protease NS2 (PubMed:21147927). Interacts with non-structural protein 4A; this interaction stabilizes the folding of NS3 serine protease (By similarity). NS3-NS4A interaction is essential for NS3 activation and allows membrane anchorage of the latter (PubMed:7769699, PubMed:8861917). NS3/NS4A complex also prevents phosphorylation of host IRF3, thus preventing the establishment of dsRNA induced antiviral state (By similarity). Interacts with host MAVS; this interaction leads to the cleavage and inhibition of host MAVS (PubMed:16177806, PubMed:16301520). Interacts with host TICAM1; this interaction leads to the cleavage and inhibition of host TICAM1 (PubMed:16177806, PubMed:16301520). Interacts with host TANK-binding kinase/TBK1; this interaction results in the inhibition of the association between TBK1 and IRF3, which leads to the inhibition of IRF3 activation (By similarity). Interacts with host RBM24 (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692242, PubMed:12692249). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).SUBUNIT Interacts with NS3 serine protease; this interaction stabilizes the folding of NS3 serine protease (PubMed:7769699, PubMed:8861917). NS3-NS4A interaction is essential for NS3 activation and allows membrane anchorage of the latter (PubMed:7769699, PubMed:8861917). Interacts with non-structural protein 5A (via N-terminus) (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692242, PubMed:12692249). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).SUBUNIT Homomultimer (PubMed:23868571). Interacts with non-structural protein NS5A (PubMed:23868571). Interacts with host PLA2G4C; this interaction likely initiates the recruitment of replication complexes to lipid droplets (By similarity). Interacts with host STING; this interaction disrupts the interaction between STING and TBK1 thereby suppressing the interferon signaling (PubMed:23542348). Interacts with host METTL22; this interaction may promote the recruitment of NS4B in the proximity of lipid droplet (PubMed:26185986). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692242, PubMed:12692249).SUBUNIT Monomer (PubMed:20926572). Homodimer; dimerization is required for RNA-binding (PubMed:20926572). Interacts with the mature core protein (By similarity). Interacts (via N-terminus) with non-structural protein 4A (By similarity). Interacts with non-structural protein 4B (PubMed:23868571). Interacts (via region D2) with RNA-directed RNA polymerase (Probable). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692242, PubMed:12692249). Interacts with host GRB2 (By similarity). Interacts with host BIN1 (PubMed:16530520). Interacts with host PIK3R1 (By similarity). Interacts with host SRCAP (PubMed:10702287). Interacts with host FKBP8 (By similarity). Interacts (via C-terminus) with host VAPB (via MSP domain) (Probable) (PubMed:22720086). Interacts with host EIF2AK2/PKR; this interaction leads to disruption of EIF2AK2 dimerization by NS5A and probably allows the virus to evade the innate immune response (Probable). Interacts (via N-terminus) with host PACSIN2 (via N-terminus); this interaction attenuates protein kinase C alpha-mediated phosphorylation of PACSIN2 by disrupting the interaction between PACSIN2 and PRKCA (PubMed:31801866). Interacts (via N-terminus) with host SRC kinase (via SH2 domain) (By similarity). Interacts with most Src-family kinases (By similarity). Interacts with host IFI27 and SKP2; promotes the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766). Interacts with host GPS2 (By similarity). Interacts with host TNFRSF21; this interaction allows the modulation by the virus of JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent manner (PubMed:28743875). Interacts (via N-terminus) with host CIDEB (via N-terminus); this interaction seems to regulate the association of HCV particles with APOE (PubMed:27282740). Interacts with host CHKA/Choline Kinase-alpha; CHKA bridges host PI4KA and NS5A and potentiates NS5A-stimulated PI4KA activity, which then facilitates the targeting of the ternary complex to the ER for viral replication (By similarity). Interacts with host SPSB2 (via C-terminus); this interaction targets NS5A for ubiquitination and degradation (PubMed:31344133). Interacts with host RAB18; this interaction may promote the association of NS5A and other replicase components with lipid droplets (By similarity). Interacts (via region D2) with host PPIA/CYPA; the interaction stimulates RNA-binding ability of NS5A and is dependent on the peptidyl-prolyl cis-trans isomerase activity of PPIA/CYPA (Probable). Interacts with host TRIM14; this interaction induces the degradation of NS5A (PubMed:27578425).SUBUNIT Homooligomer. Interacts with non-structural protein 5A (PubMed:11801599). Interacts with host VAPB (By similarity). Interacts with host PRK2/PKN2 (PubMed:15364941). Interacts with host HNRNPA1 and SEPT6; these interactions facilitate the viral replication (PubMed:17229681). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692242, PubMed:12692249).INTERACTION The C-terminal transmembrane domain of the core protein precursor contains an ER signal leading the nascent polyprotein to the ER membrane.SUBCELLULAR LOCATION Only a minor proportion of core protein is present in the nucleus (PubMed:9037030). Probably present on the surface of lipid droplets (PubMed:9037030).SUBCELLULAR LOCATION The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase (PubMed:10729138). After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (PubMed:10729138). A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain (PubMed:12065403). These events explain the final topology of the protein (PubMed:12065403).SUBCELLULAR LOCATION The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase (PubMed:10729138). After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (PubMed:10729138). A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain (PubMed:12065403). These events explain the final topology of the protein (PubMed:12065403).SUBCELLULAR LOCATION The C-terminus of p7 membrane domain acts as a signal sequence (PubMed:11907211). After cleavage by host signal peptidase, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (PubMed:11907211). ER retention of p7 is leaky and a small fraction reaches the plasma membrane (PubMed:11907211).SUBCELLULAR LOCATION Probably present on the surface of lipid droplets.SUBCELLULAR LOCATION NS3 is associated to the ER membrane through its binding to NS4A.SUBCELLULAR LOCATION Host membrane insertion occurs after processing by the NS3 protease.SUBCELLULAR LOCATION A reorientation of the N-terminus into the ER lumen occurs post-translationally (PubMed:17030859). Localized in the vicinity of host lipid droplet (PubMed:26185986).SUBCELLULAR LOCATION Host membrane insertion occurs after processing by the NS3 protease (PubMed:11744739). Localizes at the surface of lipid droplets (By similarity).SUBCELLULAR LOCATION Host membrane insertion occurs after processing by the NS3 protease.ALTERNATIVE PRODUCTS The exact location of the ribosomal frameshift is unknown. The F protein seems to be generated by a -2 ribosomal frameshift located in the vicinity of codon 11 of the core protein coding sequence. However, some F proteins may also be generated by +1 ribosomal frameshift. Since the core gene encodes alternative reading frame proteins (ARFPs), many functions depicted for the core protein might belong to the ARFPs.INDUCTION Expressed late in the infection cycle.DOMAIN The disordered N-terminus allows the interaction with several host proteins (PubMed:18992225, PubMed:25424537). This disordered region also seems to play an important role in mediating RNA chaperoning (PubMed:18033802).DOMAIN The transmembrane regions of envelope E1 and E2 glycoproteins are involved in heterodimer formation, ER localization, and assembly of these proteins.DOMAIN The transmembrane regions of envelope E1 and E2 glycoproteins are involved in heterodimer formation, ER localization, and assembly of these proteins (PubMed:11145889). Envelope E2 glycoprotein contain two highly variable regions called hypervariable region 1 and 2 (HVR1 and HVR2) (PubMed:11356980). E2 also contain two segments involved in CD81-binding (By similarity). HVR1 is implicated in the SCARB1-mediated cell entry and probably acts as a regulator of the association of particles with lipids (PubMed:22767607).DOMAIN The N-terminus of NS3 is required for the catalytic activity of protease NS2 (By similarity). The minimal catalytic region includes the C-terminus of NS2 and the N-terminus NS3 protease domain (active region NS2-3) (By similarity).DOMAIN The N-terminal one-third contains the protease activity (By similarity). This region contains a zinc atom that does not belong to the active site, but may play a structural rather than a catalytic role (By similarity). This region is essential for the activity of protease NS2, maybe by contributing to the folding of the latter (By similarity). The NTPase/helicase activity is located in the twothirds C-terminus of NS3, this domain contains the NTPase and RNA-binding regions (PubMed:1658800).DOMAIN Contains a glycine zipper region that critically contributes to the biogenesis of functional ER-derived replication organelles.DOMAIN The N-terminus acts as a membrane anchor (PubMed:15247283). The C-terminus contains a nuclear localization signal (PubMed:8982089).DOMAIN Contains a variable region called interferon sensitivity determining region (ISDR) and a variable region called variable region 3 (V3) (By similarity). ISDR and V3 may be involved in sensitivity and/or resistance to IFN-alpha therapy (By similarity).DOMAIN The SH3-binding domain is involved in the interaction with host BIN1, GRB2 and Src-family kinases.DOMAIN The structured region D1 is involved in RNA-binding.DOMAIN The first disordered region named D2 interacts with several viral and host proteins (PubMed:27194766, PubMed:27676132). The largely disordered region D3 mediates the interaction with several host proteins and is involved in virion assembly (PubMed:22720086, PubMed:26727512, PubMed:27194766).PTM Specific enzymatic cleavages in vivo yield mature proteins (PubMed:15722527, PubMed:8035505, PubMed:8189513, PubMed:8386278). The structural proteins, core, E1, E2 and p7 are produced by proteolytic processing by host signal peptidases (PubMed:15247249). 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 (PubMed:15247249, PubMed:7679746, PubMed:8035505, PubMed:8189513, PubMed:8386278). Autoprocessing between NS2 and NS3 is mediated by the NS2 cysteine protease catalytic domain and regulated by the NS3 N-terminal domain (By similarity).PTM Phosphorylated by host PKC and PKA.PTM Ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation.PTM Highly N-glycosylated.PTM Highly N-glycosylated.PTM Palmitoylation is required for NS2/3 autoprocessing and E2 recruitment to membranes.PTM Palmitoylated. This modification may play a role in its polymerization or in protein-protein interactions.PTM Cleaved by host caspases which are probably activated by the viral infection.PTM Ubiquitinated (PubMed:25683609, PubMed:27194766). Ubiquitination, most probably at Lys-2350, mediated by host IFI27 and SKP2 leads to proteasomal degradation, restricting viral infection (PubMed:27194766). Ubiquitination by host TRIM22 leads to interruption of viral replication (PubMed:25683609).PTM 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, PI4KA or RPS6KB1 kinases may be responsible for NS5A phosphorylation (By similarity). Phosphorylated NS5A is involved in viral replication (By similarity).PTM Tyrosine phosphorylation is essential for the interaction with host SRC.PTM The N-terminus is phosphorylated by host PRK2/PKN2.MISCELLANEOUS Viral particle assembly takes place at the surface of ER-derived membranes in close proximity to lipid droplets. NS2 associates with E1/E2 glycoproteins, NS3 and NS5A, which interacts with the viral RNA and core protein to promote genome encapsidation. The nucleocapsid buds at the ER membrane where E1/E2 glycoproteins are anchored and afterward associate with nascent lipid droplet to acquire APOE and APOC. Secretion of viral particles is probably regulated by viroporin p7.MISCELLANEOUS Cell culture adaptation of the virus leads to mutations in NS5A, reducing its inhibitory effect on replication.MISCELLANEOUS Exerts viral interference on hepatitis B virus when HCV and HBV coinfect the same cell, by suppressing HBV gene expression, RNA encapsidation and budding.SIMILARITY Belongs to the hepacivirus polyprotein family.CAUTION The core gene probably also codes for alternative reading frame proteins (ARFPs). Many functions depicted for the core protein might belong to the ARFPs. |
| created | [InstanceEdit:9731811] Shamovsky, Veronica, 2021-05-25 |
| description | recommendedName: Genome polyprotein component recommendedName: Core protein precursor alternativeName: Capsid protein C alternativeName: p23 /component component recommendedName: Mature core protein alternativeName: p21 /component component recommendedName: Envelope glycoprotein E1 alternativeName: gp32 alternativeName: gp35 /component component recommendedName: Envelope glycoprotein E2 alternativeName: NS1 alternativeName: gp68 alternativeName: gp70 /component component recommendedName: Viroporin p7 /component component recommendedName: Protease NS2 shortName: p23 ecNumber evidence="3"3.4.22.- alternativeName: Non-structural protein 2 shortName: NS2 /component component recommendedName: Serine protease/helicase NS3 ecNumber evidence="115 118"3.4.21.98 ecNumber evidence="47 54 92"3.6.1.15 ecNumber evidence="47 54 92"3.6.4.13 alternativeName: Hepacivirin alternativeName: fullName evidence="123"NS3 helicase alternativeName: fullName evidence="125"NS3 protease alternativeName: NS3P alternativeName: Viroporin p70 /component component recommendedName: Non-structural protein 4A shortName: NS4A alternativeName: p8 /component component recommendedName: Non-structural protein 4B shortName: NS4B alternativeName: p27 /component component recommendedName: Non-structural protein 5A shortName: NS5A alternativeName: p56/58 /component component recommendedName: RNA-directed RNA polymerase ecNumber evidence="72"2.7.7.48 alternativeName: NS5B alternativeName: p68 /component |
| geneName | POLG |
| identifier | P27958 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Activation of host autophagy by virus Apoptosis ATP-binding Capsid protein Clathrin-mediated endocytosis of virus by host Direct protein sequencing 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 innate immune response by virus Inhibition of host interferon signaling pathway by virus 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 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 Reference proteome Ribonucleoprotein Ribosomal frameshifting RNA-binding RNA-directed RNA polymerase Serine protease SH3-binding Thiol protease Transcription Transcription regulation Transferase Transmembrane Transmembrane helix Transport Ubl conjugation Viral attachment to host adhesion receptor Viral attachment to host cell Viral attachment to host entry receptor Viral envelope protein Viral immunoevasion Viral ion channel Viral nucleoprotein Viral penetration into host cytoplasm Viral RNA replication Virion Virus endocytosis by host Virus entry into host cell Zinc |
| modified | [InstanceEdit:9731858] Shamovsky, Veronica, 2021-05-25 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 |
| name | Genome polyprotein |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| secondaryIdentifier | POLG_HCV77 O36579 O36608 O36609 O36610 |
| sequenceLength | 3011 |
| species | [Species:8854152] Hepatitis C virus subtype 1a |
| (isoformParent) | [ReferenceIsoform:8970686] UniProt:P27958-1 Unknown [Hepatitis C virus subtype 1a] |
| (referenceEntity) | [EntityWithAccessionedSequence:9731863] HCV ns3 [endoplasmic reticulum membrane] [Hepatitis C virus subtype 1a] [EntityWithAccessionedSequence:9731865] HCV ns4A [endoplasmic reticulum membrane] [Hepatitis C virus subtype 1a] |
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No pathways have been reviewed or authored by UniProt:P27958 POLG (9731837)
