| IED ID | IndEnz0002011494 |
| Enzyme Type ID | protease011494 |
| 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 Fragment |
| Gene Name | |
| Organism | Hepatitis C virus (isolate HCV-KF) (HCV) |
| Taxonomic Lineage | Viruses Riboviria Orthornavirae Kitrinoviricota Flasuviricetes Amarillovirales Flaviviridae Hepacivirus Hepacivirus C unclassified Hepatitis C virus Hepatitis C virus (isolate HCV-KF) (HCV) |
| Enzyme Sequence | MSTNPKPQRKTKRNTNRRPQDVKFPGGGQIVGGVYLLTRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRAWAQPGYPWPLYGNEGLGWAGWLLSPRGSRPSWGPTDPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAPLGGASRALAHGVRVLEDGVNYATGNLPGCSFSIFLSALMSCLTTPASAYEVRNVSGIYHVTNDCSNSSIAYEAAGMIMHTPGCVPCVRENNSSRCWVALTPTLAARNASVPTTTIRRHVDLLVGAATLCSAMYVGDLCGSVFLVSQLFTFSPRRYETVQDCNCSIYPGHVSGHRMAWDMMMNWSPTAALVVSQLLRIPQAVVDMVAGAHWGVLAGLAYYSMVGNWAKVLIVMLLFAGVDGANTHTVGGTEGFATQRLTSLFALGPSQKIQLINTNGSWHINRTALNCNDSFKTGFLAALFYVHKFNASGCPEHMASCRPIDKFDQGWGPVTYAEPSISEQRPYCWHYAPRPCGTIPASEVCGPVYCFTPSPVVVGTT |
| Enzyme Length | 520 |
| Uniprot Accession Number | Q01403 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| 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 facilitated transmission to permissive cells such as hepatocytes and lymphocyte subpopulations (By similarity). {ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Chain (5); Compositional bias (1); Disulfide bond (3); Glycosylation (9); Initiator methionine (1); Modified residue (4); Motif (4); Mutagenesis (6); Non-terminal residue (1); Propeptide (1); Region (11); Site (3); Topological domain (3); Transmembrane (2) |
| Keywords | Acetylation;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;Glycoprotein;Host cytoplasm;Host endoplasmic reticulum;Host lipid droplet;Host membrane;Host mitochondrion;Host nucleus;Host-virus interaction;Interferon antiviral system evasion;Isopeptide bond;Magnesium;Membrane;Oncogene;Phosphoprotein;RNA-binding;Ribonucleoprotein;Transmembrane;Transmembrane helix;Ubl conjugation;Viral attachment to host cell;Viral envelope protein;Viral nucleoprotein;Viral penetration into host cytoplasm;Virion;Virus endocytosis by host;Virus entry into host cell |
| Interact With | |
| 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:0000269|PubMed:7815494}. 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}. |
| Modified Residue | MOD_RES 2; /note=N-acetylserine; by host; /evidence=ECO:0000250|UniProtKB:Q913V3; MOD_RES 53; /note=Phosphoserine; by host; /evidence=ECO:0000269|PubMed:7815494; MOD_RES 99; /note=Phosphoserine; by host; /evidence=ECO:0000269|PubMed:7815494; MOD_RES 116; /note=Phosphoserine; by host PKA; /evidence=ECO:0000269|PubMed:7815494 |
| 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:0000269|PubMed:7815494}.; 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}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | - |
| 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 |
| Gene Encoded By | |
| Mass | 56,477 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |