Q5EG65 (POLG_HCVGL) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 72. History...
Names and origin
|Protein names||Recommended name:|
|Organism||Hepatitis C virus (isolate Glasgow) (HCV)|
|Taxonomic identifier||329389 [NCBI]|
|Taxonomic lineage||Viruses › ssRNA positive-strand viruses, no DNA stage › Flaviviridae › Hepacivirus ›|
|Virus host||Homo sapiens (Human) [TaxID: 9606]|
|Sequence length||829 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110bin the cytoplasm. Also 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 NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) By similarity.
E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a 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. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. 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.
P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity By similarity.
Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation By similarity.
Activity of auto-protease NS2-3 is dependent on zinc ions and completely inhibited by EDTA By similarity.
Core protein is a homomultimer that binds the C-terminal part of E1 and interacts with numerous cellular proteins. Interaction with human STAT1 SH2 domain seems to result in decreased STAT1 phosphorylation, leading to decreased IFN-stimulated gene transcription. In addition to blocking the formation of phosphorylated STAT1, the core protein also promotes ubiquitin-mediated proteasome-dependent degradation of STAT1. Interacts with, and constitutively activates human STAT3. Associates with human LTBR and TNFRSF1A receptors and possibly induces apoptosis. Binds to human SP110 isoform 3/Sp110b HNRPK, C1QR1, YWHAE, UBE3A/E6AP, DDX3X, APOA2 and RXRA proteins. Interacts with human CREB3 nuclear transcription protein, triggering cell transformation. May interact with human p53. Also binds human cytokeratins KRT8, KRT18, KRT19 and VIM (vimentin). E1 and E2 glycoproteins form a heterodimer that binds to human LDLR, CD81 and SCARB1 receptors. E2 binds and inhibits human EIF2AK2/PKR. Also binds human CD209/DC-SIGN and CLEC4M/DC-SIGNR. p7 forms a homoheptamer in vitro By similarity. Ref.2
Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein By similarity. Host mitochondrion membrane; Single-pass type I membrane protein By similarity. Host lipid droplet By similarity. Note: The C-terminal transmembrane domain of core protein p21 contains an ER signal leading the nascent polyprotein to the ER membrane. Only a minor proportion of core protein is present in the nucleus and an unknown proportion is secreted By similarity. Ref.3 Ref.5
Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein Potential. Host endoplasmic reticulum membrane; Single-pass type I membrane protein By similarity. Note: The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase. After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain. These events explain the final topology of the protein. ER retention of E1 is leaky and, in overexpression conditions, only a small fraction reaches the plasma membrane By similarity. Ref.3 Ref.5
Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein Potential. Host endoplasmic reticulum membrane; Single-pass type I membrane protein By similarity. Note: The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase. After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain. These events explain the final topology of the protein. ER retention of E2 is leaky and, in overexpression conditions, only a small fraction reaches the plasma membrane By similarity. Ref.3 Ref.5
p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein By similarity. Host cell membrane By similarity. Note: The C-terminus of p7 membrane domain acts as a signal sequence. After cleavage by host signal peptidase, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. Only a fraction localizes to the plasma membrane By similarity. Ref.3 Ref.5
The transmembrane regions of envelope E1 and E2 glycoproteins are involved in heterodimer formation, ER localization, and assembly of these proteins. Envelope E2 glycoprotein contain two highly variable regions called hypervariable region 1 and 2 (HVR1 and HVR2) and two CD81-binding sites. HVR1 is implicated in the SCARB1-mediated cell entry. HVR2 and CD81-binding sites may be involved in sensitivity and/or resistance to IFN-alpha therapy By similarity.
Specific enzymatic cleavages in vivo yield mature proteins. The structural proteins, core, E1, E2 and p7 are produced by proteolytic processing by host signal peptidases. The core protein is synthesized as a 21 kDa precursor which is retained in the ER membrane through the hydrophobic signal peptide. Cleavage by the signal peptidase releases the 19 kDa mature core protein. The other proteins (p7 and NS2-3) are cleaved by the viral proteases By similarity. Ref.3
Envelope E1 and E2 glycoproteins are highly N-glycosylated By similarity.
Core protein is phosphorylated by host PKC and PKA By similarity.
Core protein is ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation By similarity.
Core protein exerts viral interference on hepatitis B virus when HCV and HBV coinfect the same cell, by suppressing HBV gene expression, RNA encapsidation and budding By similarity.
Belongs to the hepacivirus polyprotein family.
The core gene probably also codes for alternative reading frame proteins (ARFPs). Many functions depicted for the core protein might belong to the ARFPs.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed; by host By similarity|
|Chain||2 – 191||190||Core protein p21||PRO_0000037559|
|Chain||2 – 177||176||Core protein p19 By similarity||PRO_0000037560|
|Propeptide||178 – 191||14||ER anchor for the core protein, removed in mature form by host signal peptidase By similarity||PRO_0000037561|
|Chain||192 – 383||192||Envelope glycoprotein E1 Potential||PRO_0000037562|
|Chain||384 – 746||363||Envelope glycoprotein E2 Potential||PRO_0000037563|
|Chain||747 – 809||63||p7 By similarity||PRO_0000037564|
|Chain||810 – ›829||›20||Protease NS2-3 Potential||PRO_0000037565|
|Topological domain||2 – 168||167||Cytoplasmic Potential|
|Transmembrane||169 – 189||21||Helical; Potential|
|Topological domain||190 – 358||169||Lumenal Potential|
|Transmembrane||359 – 379||21||Helical; Potential|
|Topological domain||380 – 725||346||Lumenal Potential|
|Transmembrane||726 – 746||21||Helical; Potential|
|Topological domain||747 – 757||11||Lumenal Potential|
|Transmembrane||758 – 778||21||Helical; Potential|
|Topological domain||779 – 782||4||Cytoplasmic Potential|
|Transmembrane||783 – 803||21||Helical; Potential|
|Topological domain||804 – 813||10||Lumenal Potential|
|Transmembrane||814 – ›829||›16||Helical; Potential|
|Region||2 – 59||58||Interaction with DDX3X By similarity|
|Region||2 – 23||22||Interaction with STAT1 By similarity|
|Region||122 – 173||52||Interaction with APOA2 By similarity|
|Region||150 – 159||10||Mitochondrial targeting signal By similarity|
|Region||164 – 167||4||Important for lipid droplets localization By similarity|
|Region||265 – 296||32||Fusion peptide Potential|
|Region||385 – 411||27||HVR1 By similarity|
|Region||475 – 481||7||HVR2 By similarity|
|Region||482 – 494||13||CD81-binding 1 Potential|
|Region||522 – 553||32||CD81-binding 2 Potential|
|Region||660 – 671||12||PKR/eIF2-alpha phosphorylation homology domain (PePHD)|
|Motif||5 – 13||9||Nuclear localization signal Potential|
|Motif||38 – 43||6||Nuclear localization signal Potential|
|Motif||58 – 64||7||Nuclear localization signal Potential|
|Motif||66 – 71||6||Nuclear localization signal Potential|
|Compositional bias||476 – 479||4||Poly-Gly|
|Compositional bias||796 – 803||8||Poly-Leu|
|Site||177 – 178||2||Cleavage; by host signal peptidase By similarity|
|Site||191 – 192||2||Cleavage; by host signal peptidase Potential|
|Site||383 – 384||2||Cleavage; by host signal peptidase Potential|
|Site||746 – 747||2||Cleavage; by host signal peptidase By similarity|
|Site||809 – 810||2||Cleavage; by host signal peptidase By similarity|
Amino acid modifications
|Modified residue||2||1||N-acetylserine; by host By similarity|
|Modified residue||53||1||Phosphoserine; by host By similarity|
|Modified residue||99||1||Phosphoserine; by host By similarity|
|Modified residue||116||1||Phosphoserine; by host PKA By similarity|
|Glycosylation||196||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||209||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||234||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||305||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||417||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||423||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||430||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||448||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||540||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||556||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||576||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||623||1||N-linked (GlcNAc...); by host Potential|
|Glycosylation||645||1||N-linked (GlcNAc...); by host Potential|
|Mutagenesis||180 – 184||5||ALLSC → VLLLV: Complete loss of processing. Ref.3|
Helix Strand Turn
|Beta strand||414 – 416||3|
|Beta strand||419 – 421||3|
|||"Covalent interactions are not required to permit or stabilize the non-covalent association of hepatitis C virus glycoproteins E1 and E2."|
Patel J., Patel A.H., McLauchlan J.
J. Gen. Virol. 80:1681-1690(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
|||"Hepatitis C virus core protein interacts with a human DEAD box protein DDX3."|
Owsianka A.M., Patel A.H.
Virology 257:330-340(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION OF CORE PROTEIN WITH HUMAN DDX3X.
|||"Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets."|
McLauchlan J., Lemberg M.K., Hope G., Martoglio B.
EMBO J. 21:3980-3988(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: CLEAVAGE OF CORE PROTEIN BY THE SIGNAL PEPTIDASE, SUBCELLULAR LOCATION, MUTAGENESIS OF 180-ALA--CYS-184.
|||"Properties of the hepatitis C virus core protein: a structural protein that modulates cellular processes."|
J. Viral Hepat. 7:2-14(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
|||"Structural biology of hepatitis C virus."|
Penin F., Dubuisson J., Rey F.A., Moradpour D., Pawlotsky J.-M.
Hepatology 39:5-19(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW, SUBCELLULAR LOCATION.
|+||Additional computationally mapped references.|
|AY885238 Genomic RNA. Translation: AAW78019.1.|
3D structure databases
|SMR||Q5EG65. Positions 2-45. |
Protocols and materials databases
Family and domain databases
|InterPro||IPR002521. HCV_core_C. |
|Pfam||PF01543. HCV_capsid. 1 hit. |
PF01542. HCV_core. 1 hit.
PF01539. HCV_env. 1 hit.
PF01560. HCV_NS1. 1 hit.
|ProDom||PD001388. HCV_env. 1 hit. |
[Graphical view] [Entries sharing at least one domain]
|Accession||Primary (citable) accession number: Q5EG65|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Viral Protein Annotation Program|