| Structural highlights
Function
[POLG_HCVH] 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/Sp110b in 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).[1] 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).[2] P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine (By similarity). Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity.[3] Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity).[4] NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand (By similarity). Cleaves and inhibits the host antiviral protein MAVS.[5] NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex. NS4B polymerization or in protein-protein interactions activity may contribute to its function in membranous web formation.[6] NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity).[7] NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication.[8]
Publication Abstract from PubMed
The high mutation rate of hepatitis C virus allows it to rapidly evade the humoral immune response. However, certain epitopes in the envelope glycoproteins cannot vary without compromising virus viability. Antibodies targeting these epitopes are resistant to viral escape from neutralization and understanding their binding-mode is important for vaccine design. Human monoclonal antibodies HC84-1 and HC84-27 target conformational epitopes overlapping the CD81 receptor-binding site, formed by segments aa434-446 and aa610-619 within the major HCV glycoprotein E2. No neutralization escape was yet observed for these antibodies. We report here the crystal structures of their Fab fragments in complex with a synthetic peptide comprising aa434-446. The structures show that the peptide adopts an alpha-helical conformation with the main contact residues F(442) and Y(443) forming a hydrophobic protrusion. The peptide retained its conformation in both complexes, independently of crystal packing, indicating that it reflects a surface feature of the folded glycoprotein that is exposed similarly on the virion. The same residues of E2 are also involved in interaction with CD81, suggesting that the cellular receptor binds the same surface feature and potential escape mutants critically compromise receptor binding. In summary, our results identify a critical structural motif at the E2 surface, which is essential for virus propagation and therefore represents an ideal candidate for structure-based immunogen design for vaccine development.
Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.,Krey T, Meola A, Keck ZY, Damier-Piolle L, Foung SK, Rey FA PLoS Pathog. 2013 May;9(5):e1003364. doi: 10.1371/journal.ppat.1003364. Epub 2013, May 16. PMID:23696737[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP. Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol. 2006 Sep;87(Pt 9):2583-93. PMID:16894197 doi:87/9/2583
- ↑ Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP. Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol. 2006 Sep;87(Pt 9):2583-93. PMID:16894197 doi:87/9/2583
- ↑ Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP. Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol. 2006 Sep;87(Pt 9):2583-93. PMID:16894197 doi:87/9/2583
- ↑ Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP. Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol. 2006 Sep;87(Pt 9):2583-93. PMID:16894197 doi:87/9/2583
- ↑ Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP. Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol. 2006 Sep;87(Pt 9):2583-93. PMID:16894197 doi:87/9/2583
- ↑ Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP. Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol. 2006 Sep;87(Pt 9):2583-93. PMID:16894197 doi:87/9/2583
- ↑ Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP. Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol. 2006 Sep;87(Pt 9):2583-93. PMID:16894197 doi:87/9/2583
- ↑ Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP. Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol. 2006 Sep;87(Pt 9):2583-93. PMID:16894197 doi:87/9/2583
- ↑ Krey T, Meola A, Keck ZY, Damier-Piolle L, Foung SK, Rey FA. Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape. PLoS Pathog. 2013 May;9(5):e1003364. doi: 10.1371/journal.ppat.1003364. Epub 2013, May 16. PMID:23696737 doi:10.1371/journal.ppat.1003364
|
