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O92530

- POLG_HCVVN

UniProt

O92530 - POLG_HCVVN

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Protein

Genome polyprotein

Gene
N/A
Organism
Hepatitis C virus genotype 6d (isolate VN235) (HCV)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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.
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.
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. Cleaves and inhibits the host antiviral protein MAVS By similarity.
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 By similarity.
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.
NS5B is an RNA-dependent RNA polymerase that plays an essential role in the virus replication By similarity.

Catalytic activityi

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'.
Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1).
NTP + H2O = NDP + phosphate.
ATP + H2O = ADP + phosphate.

Cofactori

Binds 1 zinc ion per NS3 protease domain By similarity.
Binds 1 zinc ion per NS5A N-terminal domain By similarity.

Enzyme regulationi

Activity of auto-protease NS2-3 is dependent on zinc ions and completely inhibited by EDTA. Serine protease NS3 is also activated by zinc ions By similarity.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei177 – 1782Cleavage; by host signal peptidase By similarity
Sitei191 – 1922Cleavage; by host signal peptidase Reviewed prediction
Sitei383 – 3842Cleavage; by host signal peptidase Reviewed prediction
Sitei744 – 7452Cleavage; by host signal peptidase By similarity
Sitei807 – 8082Cleavage; by host signal peptidase By similarity
Active sitei950 – 9501For protease NS2-3 activity; shared with dimeric partner By similarity
Active sitei970 – 9701For protease NS2-3 activity; shared with dimeric partner By similarity
Active sitei991 – 9911For protease NS2-3 activity; shared with dimeric partner By similarity
Sitei1024 – 10252Cleavage; by protease NS2-3 Reviewed prediction
Active sitei1081 – 10811Charge relay system; for serine protease NS3 activity By similarity
Active sitei1105 – 11051Charge relay system; for serine protease NS3 activity By similarity
Metal bindingi1121 – 11211Zinc By similarity
Metal bindingi1123 – 11231Zinc By similarity
Active sitei1163 – 11631Charge relay system; for serine protease NS3 activity By similarity
Metal bindingi1169 – 11691Zinc By similarity
Metal bindingi1173 – 11731Zinc By similarity
Sitei1655 – 16562Cleavage; by serine protease NS3 Reviewed prediction
Sitei1709 – 17102Cleavage; by serine protease NS3 Reviewed prediction
Sitei1970 – 19712Cleavage; by serine protease NS3 Reviewed prediction
Metal bindingi2009 – 20091Zinc By similarity
Metal bindingi2027 – 20271Zinc By similarity
Metal bindingi2029 – 20291Zinc By similarity
Metal bindingi2050 – 20501Zinc By similarity
Sitei2422 – 24232Cleavage; by serine protease NS3 Reviewed prediction

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi1228 – 12358ATP Reviewed prediction

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. ATP-dependent helicase activity Source: InterPro
  3. cysteine-type endopeptidase activity Source: InterPro
  4. ion channel activity Source: UniProtKB-KW
  5. RNA binding Source: UniProtKB-KW
  6. RNA-directed RNA polymerase activity Source: UniProtKB-KW
  7. serine-type endopeptidase activity Source: InterPro
  8. serine-type exopeptidase activity Source: InterPro
  9. structural molecule activity Source: InterPro
  10. zinc ion binding Source: InterPro

GO - Biological processi

  1. apoptotic process Source: UniProtKB-KW
  2. clathrin-mediated endocytosis of virus by host cell Source: UniProtKB-KW
  3. fusion of virus membrane with host endosome membrane Source: UniProtKB-KW
  4. induction by virus of host autophagy Source: UniProtKB-KW
  5. modulation by virus of host G1/S transition checkpoint Source: UniProtKB-KW
  6. pore formation by virus in membrane of host cell Source: UniProtKB-KW
  7. protein oligomerization Source: UniProtKB-KW
  8. regulation of transcription, DNA-templated Source: UniProtKB-KW
  9. suppression by virus of host MAVS activity Source: UniProtKB-KW
  10. suppression by virus of host STAT1 activity Source: UniProtKB-KW
  11. suppression by virus of host TRAF activity Source: UniProtKB-KW
  12. suppression by virus of host type I interferon-mediated signaling pathway Source: UniProtKB-KW
  13. transcription, DNA-templated Source: UniProtKB-KW
  14. transformation of host cell by virus Source: InterPro
  15. viral RNA genome replication Source: InterPro
  16. virion attachment to host cell Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Helicase, Hydrolase, Ion channel, Nucleotidyltransferase, Protease, Ribonucleoprotein, RNA-directed RNA polymerase, Serine protease, Thiol protease, Transferase, Viral ion channel

Keywords - Biological processi

Activation of host autophagy by virus, Apoptosis, Clathrin-mediated endocytosis of virus by host, Fusion of virus membrane with host endosomal membrane, Fusion of virus membrane with host membrane, G1/S host cell cycle checkpoint dysregulation by virus, Host-virus interaction, 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 transport, Modulation of host cell cycle by virus, Transcription, Transcription regulation, Transport, Viral attachment to host cell, Viral immunoevasion, Viral penetration into host cytoplasm, Viral RNA replication, Virus endocytosis by host, Virus entry into host cell

Keywords - Ligandi

ATP-binding, Metal-binding, Nucleotide-binding, RNA-binding, Viral nucleoprotein, Zinc

Protein family/group databases

MEROPSiC18.001.
TCDBi1.A.53.1.6. the hepatitis c virus p7 viroporin cation-selective channel (hcv-p7) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Genome polyprotein
Cleaved into the following 11 chains:
Alternative name(s):
Capsid protein C
p21
Alternative name(s):
gp32
gp35
Alternative name(s):
NS1
gp68
gp70
Protease NS2-3 (EC:3.4.22.-)
Short name:
p23
Alternative name(s):
Hepacivirin
NS3P
p70
Alternative name(s):
p8
Alternative name(s):
p27
Alternative name(s):
p56
Alternative name(s):
NS5B
p68
OrganismiHepatitis C virus genotype 6d (isolate VN235) (HCV)
Taxonomic identifieri356422 [NCBI]
Taxonomic lineageiVirusesssRNA positive-strand viruses, no DNA stageFlaviviridaeHepacivirus
Virus hostiHomo sapiens (Human) [TaxID: 9606]
ProteomesiUP000008103: Genome

Subcellular locationi

Chain 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.1 Publication
Chain Core protein p19 : Virion By similarity. Host cytoplasm By similarity. Host nucleus By similarity. Secreted By similarity 1 Publication
Chain Envelope glycoprotein E1 : Virion membrane; Single-pass type I membrane protein Reviewed prediction. 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.1 Publication
Chain Envelope glycoprotein E2 : Virion membrane; Single-pass type I membrane protein Reviewed prediction. 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.1 Publication
Chain 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.1 Publication
Chain Protease NS2-3 : Host endoplasmic reticulum membrane; Multi-pass membrane protein Reviewed prediction 1 Publication
Chain Serine protease NS3 : Host endoplasmic reticulum membrane; Peripheral membrane protein By similarity
Note: NS3 is associated to the ER membrane through its binding to NS4A.1 Publication
Chain Non-structural protein 4A : Host endoplasmic reticulum membrane; Single-pass type I membrane protein Reviewed prediction
Note: Host membrane insertion occurs after processing by the NS3 protease.1 Publication
Chain Non-structural protein 4B : Host endoplasmic reticulum membrane; Multi-pass membrane protein By similarity 1 Publication
Chain Non-structural protein 5A : Host endoplasmic reticulum membrane; Peripheral membrane protein By similarity. Host cytoplasmhost perinuclear region By similarity. Host mitochondrion By similarity
Note: Host membrane insertion occurs after processing by the NS3 protease.1 Publication
Chain RNA-directed RNA polymerase : Host endoplasmic reticulum membrane; Single-pass type I membrane protein Reviewed prediction
Note: Host membrane insertion occurs after processing by the NS3 protease.1 Publication

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini2 – 168167Cytoplasmic Reviewed predictionAdd
BLAST
Transmembranei169 – 18921Helical; Reviewed predictionAdd
BLAST
Topological domaini190 – 358169Lumenal Reviewed predictionAdd
BLAST
Transmembranei359 – 37921Helical; Reviewed predictionAdd
BLAST
Topological domaini380 – 723344Lumenal Reviewed predictionAdd
BLAST
Transmembranei724 – 74421Helical; Reviewed predictionAdd
BLAST
Topological domaini745 – 75511Lumenal Reviewed predictionAdd
BLAST
Transmembranei756 – 77621Helical; Reviewed predictionAdd
BLAST
Topological domaini777 – 7804Cytoplasmic Reviewed prediction
Transmembranei781 – 80121Helical; Reviewed predictionAdd
BLAST
Topological domaini802 – 81110Lumenal Reviewed prediction
Transmembranei812 – 83221Helical; Reviewed predictionAdd
BLAST
Topological domaini833 – 87947Cytoplasmic Reviewed predictionAdd
BLAST
Transmembranei880 – 90021Helical; Reviewed predictionAdd
BLAST
Topological domaini901 – 92626Lumenal Reviewed predictionAdd
BLAST
Transmembranei927 – 94721Helical; Reviewed predictionAdd
BLAST
Topological domaini948 – 1655708Cytoplasmic Reviewed predictionAdd
BLAST
Transmembranei1656 – 167621Helical; Reviewed predictionAdd
BLAST
Topological domaini1677 – 1803127Cytoplasmic Reviewed predictionAdd
BLAST
Transmembranei1804 – 182421Helical; Reviewed predictionAdd
BLAST
Topological domaini1825 – 18262Lumenal Reviewed prediction
Transmembranei1827 – 184721Helical; Reviewed predictionAdd
BLAST
Topological domaini1848 – 18481Cytoplasmic Reviewed prediction
Transmembranei1849 – 186921Helical; Reviewed predictionAdd
BLAST
Topological domaini1870 – 187910Lumenal Reviewed prediction
Transmembranei1880 – 190021Helical; Reviewed predictionAdd
BLAST
Topological domaini1901 – 197070Cytoplasmic Reviewed predictionAdd
BLAST
Intramembranei1971 – 200030 By similarityAdd
BLAST
Topological domaini2001 – 2992992Cytoplasmic Reviewed predictionAdd
BLAST
Transmembranei2993 – 301321Helical; By similarityAdd
BLAST

GO - Cellular componenti

  1. host cell endoplasmic reticulum membrane Source: UniProtKB-SubCell
  2. host cell lipid particle Source: UniProtKB-SubCell
  3. host cell mitochondrial membrane Source: UniProtKB-SubCell
  4. host cell nucleus Source: UniProtKB-SubCell
  5. host cell perinuclear region of cytoplasm Source: UniProtKB-SubCell
  6. host cell plasma membrane Source: UniProtKB-SubCell
  7. integral component of membrane Source: UniProtKB-KW
  8. integral to membrane of host cell Source: UniProtKB-KW
  9. ribonucleoprotein complex Source: UniProtKB-KW
  10. viral envelope Source: UniProtKB-KW
  11. viral nucleocapsid Source: UniProtKB-KW
  12. virion membrane Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Capsid protein, Host cell membrane, Host cytoplasm, Host endoplasmic reticulum, Host lipid droplet, Host membrane, Host mitochondrion, Host nucleus, Membrane, Secreted, Viral envelope protein, Virion

Pathology & Biotechi

Keywords - Diseasei

Oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed; by host By similarity
Chaini2 – 191190Core protein p21 Reviewed predictionPRO_0000045712Add
BLAST
Chaini2 – 177176Core protein p19 By similarityPRO_0000045713Add
BLAST
Propeptidei178 – 19114ER anchor for the core protein, removed in mature form by host signal peptidase By similarityPRO_0000045714Add
BLAST
Chaini192 – 383192Envelope glycoprotein E1 Reviewed predictionPRO_0000045715Add
BLAST
Chaini384 – 744361Envelope glycoprotein E2 Reviewed predictionPRO_0000045716Add
BLAST
Chaini745 – 80763p7 By similarityPRO_0000045717Add
BLAST
Chaini808 – 1024217Protease NS2-3 Reviewed predictionPRO_0000045718Add
BLAST
Chaini1025 – 1655631Serine protease NS3 Reviewed predictionPRO_0000045719Add
BLAST
Chaini1656 – 170954Non-structural protein 4A Reviewed predictionPRO_0000045720Add
BLAST
Chaini1710 – 1970261Non-structural protein 4B Reviewed predictionPRO_0000045721Add
BLAST
Chaini1971 – 2422452Non-structural protein 5A Reviewed predictionPRO_0000045722Add
BLAST
Chaini2423 – 3013591RNA-directed RNA polymerase Reviewed predictionPRO_0000045723Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserine; by host By similarity
Modified residuei53 – 531Phosphoserine; by host By similarity
Modified residuei99 – 991Phosphoserine; by host By similarity
Modified residuei116 – 1161Phosphoserine; by host PKA By similarity
Glycosylationi196 – 1961N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi209 – 2091N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi234 – 2341N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi250 – 2501N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi305 – 3051N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi417 – 4171N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi423 – 4231N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi430 – 4301N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi448 – 4481N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi476 – 4761N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi533 – 5331N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi557 – 5571N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi621 – 6211N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi643 – 6431N-linked (GlcNAc...); by host Reviewed prediction
Lipidationi1970 – 19701S-palmitoyl cysteine; by host By similarity
Disulfide bondi2112 ↔ 2160 By similarity
Modified residuei2192 – 21921Phosphoserine; by host; in p56 By similarity
Modified residuei2195 – 21951Phosphoserine; by host; in p58 By similarity
Modified residuei2199 – 21991Phosphoserine; by host; in p58 By similarity
Modified residuei2202 – 22021Phosphoserine; by host; in p58 By similarity

Post-translational modificationi

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, NS2-3, NS3, NS4A, NS4B, NS5A and NS5B) are cleaved by the viral proteases By similarity.
Envelope E1 and E2 glycoproteins are highly N-glycosylated By similarity.
Core protein is phosphorylated by host PKC and PKA By similarity.
NS5A is phosphorylated in a basal form termed p56. p58 is a hyperphosphorylated form of p56. p56 and p58 coexist in the cell in roughly equivalent amounts. Hyperphosphorylation is dependent on the presence of NS4A. Human AKT1, RPS6KB1/p70S6K, MAP2K1/MEK1, MAP2K6/MKK6 and CSNK1A1/CKI-alpha kinases may be responsible for NS5A phosphorylation By similarity.
NS4B is palmitoylated. This modification may play a role in its polymerization or in protein-protein interactions By similarity.
The N-terminus of a fraction of NS4B molecules seems to be relocated post-translationally from the cytoplasm to the ER lumen, with a 5th transmembrane segment. The C-terminus of NS2 may be lumenal with a fourth transmembrane segment By similarity.
Core protein is ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation By similarity.

Keywords - PTMi

Acetylation, Disulfide bond, Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein, Ubl conjugation

Interactioni

Subunit structurei

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, CLDN1, 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. NS2 forms a homodimer containing a pair of composite active sites at the dimerization interface. NS2 seems to interact with all other non-structural (NS) proteins. NS4A interacts with NS3 serine protease and stabilizes its folding. NS3-NS4A complex is essential for the activation of the latter and allows membrane anchorage of NS3. NS3 interacts with human TANK-binding kinase TBK1 and MAVS. NS4B and NS5A form homodimers and seem to interact with all other non-structural (NS) proteins. NS5A also interacts with human EIF2AK2/PKR, FKBP8, GRB2, BIN1, PIK3R1, SRCAP, VAPB and with most Src-family kinases. NS5B is a homooligomer and interacts with human VAPB, HNRNPA1 and SEPT6 By similarity.1 Publication

Structurei

3D structure databases

ProteinModelPortaliO92530.
SMRiO92530. Positions 16-45, 900-1024, 1027-1655, 1971-2001, 2006-2168, 2423-2985.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini901 – 1024124Peptidase C18Add
BLAST
Domaini1215 – 1367153Helicase ATP-bindingAdd
BLAST
Domaini1374 – 1536163Helicase C-terminalAdd
BLAST
Domaini2636 – 2754119RdRp catalyticAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni2 – 5958Interaction with DDX3X By similarityAdd
BLAST
Regioni2 – 2322Interaction with STAT1 By similarityAdd
BLAST
Regioni122 – 17352Interaction with APOA2 By similarityAdd
BLAST
Regioni150 – 15910Mitochondrial targeting signal By similarity
Regioni164 – 1674Important for lipid droplets localization By similarity
Regioni265 – 29632Fusion peptide Reviewed predictionAdd
BLAST
Regioni385 – 41127HVR1 By similarityAdd
BLAST
Regioni483 – 49513CD81-binding 1 Reviewed predictionAdd
BLAST
Regioni523 – 55432CD81-binding 2 Reviewed predictionAdd
BLAST
Regioni658 – 66912PKR/eIF2-alpha phosphorylation homology domain (PePHD) By similarityAdd
BLAST
Regioni1677 – 168812NS3-binding (by NS4A) Reviewed predictionAdd
BLAST
Regioni2118 – 2331214Transcriptional activation Reviewed predictionAdd
BLAST
Regioni2118 – 220689FKBP8-binding Reviewed predictionAdd
BLAST
Regioni2198 – 224851Basal phosphorylation By similarityAdd
BLAST
Regioni2208 – 227366PKR-binding Reviewed predictionAdd
BLAST
Regioni2247 – 230559NS4B-binding Reviewed predictionAdd
BLAST
Regioni2350 – 242273Basal phosphorylation By similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi5 – 139Nuclear localization signal Reviewed prediction
Motifi38 – 436Nuclear localization signal Reviewed prediction
Motifi58 – 647Nuclear localization signal Reviewed prediction
Motifi66 – 716Nuclear localization signal Reviewed prediction
Motifi1314 – 13174DECH box By similarity
Motifi2321 – 23244SH3-binding Reviewed prediction
Motifi2326 – 23349Nuclear localization signal Reviewed prediction

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi794 – 8018Poly-Leu
Compositional biasi2275 – 232652Pro-richAdd
BLAST
Compositional biasi2994 – 30018Poly-Leu

Domaini

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 a highly variable region called hypervariable region 1 (HVR1). E2 also contains two segments involved in CD81-binding. HVR1 is implicated in the SCARB1-mediated cell entry. CD81-binding regions may be involved in sensitivity and/or resistance to IFN-alpha therapy By similarity.
The N-terminus of NS5A acts as membrane anchor. The central part of NS5A seems to be intrinsically disordered and interacts with NS5B and host PKR By similarity.
The SH3-binding domain of NS5A is involved in the interaction with human Bin1, GRB2 and Src-family kinases By similarity.
The N-terminal one-third of serine protease NS3 contains the protease activity. This region contains a zinc atom that does not belong to the active site, but may play a structural rather than a catalytic role. This region is essential for the activity of protease NS2-3, maybe by contributing to the folding of the latter. The helicase activity is located in the C-terminus of NS3 By similarity.

Sequence similaritiesi

Keywords - Domaini

SH3-binding, Transmembrane, Transmembrane helix

Family and domain databases

Gene3Di3.40.50.300. 2 hits.
InterProiIPR011492. DEAD_Flavivir.
IPR002521. HCV_core_C.
IPR002522. HCV_core_N.
IPR002519. HCV_env.
IPR002531. HCV_NS1.
IPR002518. HCV_NS2.
IPR000745. HCV_NS4a.
IPR001490. HCV_NS4b.
IPR002868. HCV_NS5a.
IPR013193. HCV_NS5a_1B_dom.
IPR024350. HCV_NS5a_C.
IPR014001. Helicase_ATP-bd.
IPR001650. Helicase_C.
IPR013192. NS5A_1a.
IPR027417. P-loop_NTPase.
IPR004109. Peptidase_S29.
IPR007094. RNA-dir_pol_PSvirus.
IPR002166. RNA_pol_HCV.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]
PfamiPF07652. Flavi_DEAD. 1 hit.
PF01543. HCV_capsid. 1 hit.
PF01542. HCV_core. 1 hit.
PF01539. HCV_env. 1 hit.
PF01560. HCV_NS1. 1 hit.
PF01538. HCV_NS2. 1 hit.
PF01006. HCV_NS4a. 1 hit.
PF01001. HCV_NS4b. 1 hit.
PF01506. HCV_NS5a. 1 hit.
PF08300. HCV_NS5a_1a. 1 hit.
PF08301. HCV_NS5a_1b. 1 hit.
PF12941. HCV_NS5a_C. 1 hit.
PF02907. Peptidase_S29. 1 hit.
PF00998. RdRP_3. 1 hit.
[Graphical view]
ProDomiPD001388. HCV_env. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SMARTiSM00487. DEXDc. 1 hit.
[Graphical view]
SUPFAMiSSF50494. SSF50494. 1 hit.
SSF52540. SSF52540. 2 hits.
PROSITEiPS51693. HCV_NS2_PRO. 1 hit.
PS51192. HELICASE_ATP_BIND_1. 1 hit.
PS51194. HELICASE_CTER. 1 hit.
PS50507. RDRP_SSRNA_POS. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

O92530-1 [UniParc]FASTAAdd to Basket

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MSTLPKPQKR NQRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRATR     50
KTSERSQPRG RRQPIPKARR QTGRTWAQPG YPWPLYGNEG CGWMGWLLSP 100
RGSRPHWGPN DPRRRSRNLG KVIDTLTCGF ADLMGYIPVV GAPLGGVAAA 150
LAHGVRAVED GINYATGNLP GCSFSIFLLA LLSCLTTPAS AVHYANKSGI 200
YHLTNDCPNS SIVYEAEDFI MHLPGCVPCI KSGNGSSCWL PATLTIAVPN 250
ASIPVRGFRR HVDLMVGAAA FCSAMYVGDL CGGIFLVGQL FSFNPRRHWV 300
VQDCNCSIYV GHITGHRMAW DMMMNWSPTA TLVLSYVMRI PQVIMDIFTG 350
GHWGILAGIL YYSMVANWAK VLCILFLFAG VDATTRTTGA QAARATLGFT 400
GLFQTGAKQN IHLINTNGSW HINRTALNCN DSLNTGFMAA LFYLHKFNST 450
GCPERLSACK SITQFAQGWG PVTYANVSGS SEDRPYCWHY APRPCGVVSA 500
RSVCGPVYCF TPSPVVVGTT DRRGVPTYTW GENESDVFLL ESLRPPAGAW 550
YGCTWMNSTG YTKTCGAPPC HIGPPDQFCP TDCFRKHPEA TYRKCGSGPW 600
LTPRCLVDYP YRLWHYPCTV NYTIHKVRLF INGLEHRFDA ACNWTRGERC 650
ELEDRDRIEM SPLLFSTTEL AILPCSFTTM PALSTGLVHL HQNIVDIQYL 700
YGLAPALVSW AVRWEYVVLA FLLLADARIC ACLWMVLLIS QVEAALENLI 750
VLNAASAASS QGWIYCLVFI CCAWYIKGRV VPGATYAILH LWPLLLLVLA 800
LPQRAYAQDR EQGASIGVVV IAAITIFTLT PAYKTMLVHF LWWNQYFIAR 850
SEALIQQWVP SLRVRGGRDA VILLTCLLHP SLGFDITKML LALLGPLYLL 900
QVSLLRVPYY VRAHALLRVC ILVRRVAGGK YIQAALLKLG AWTGTYIYDH 950
LAPLSTWASD GLRDLAVAVE PVTFSPMEKK IITWGADTAA CGDILAGLPV 1000
SARLGHLLFL GPADDMKSMG WRLLAPITAY CQQTRGLLGT IVTSLTGRDR 1050
NVVEGEIQVL STATQSFLGT AINGVMWTVY HGAGSKTLAG PKGPVCQMYT 1100
NVDQDMVGWP APPGTRSLTP CTCGASDLYL VTRNADVIPA RRRGDTRAGL 1150
LSPRPLSTLK GSSGGPLMCP SDHVVGLFRA AVCTRGVAKA LDFVPVENME 1200
TTMRSPVFTD NSTPPAVPQT YQVGYLHAPT GSGKSTKVPA AYASQGYKVL 1250
VLNPSVAATL GFGSYMSTAH GIDPNIRTGV RTITTGGPIT YSTYGKFLAD 1300
GGCSGGAYDI IICDECHSTD PTTVLGIGTV LDQAETAGVR LTVLATATPP 1350
GSVTVPHPNI TETALPSTGE VPFYGKAIPL ECIKGGRHLI FCHSKKKCDE 1400
LAKQLRTLGL NAVAFYRGVD VSVIPTAGDV VVCATDALMT GYTGDFDSVI 1450
DCNVAVTQIV DFSLDPTFSI ETTTVPQDAV ARSQRRGRTG RGKPGVYRYV 1500
SQGERPSGMF DTVVLCEAYD VGCAWYELTP SETTVRLRAY LNTPGLPVCQ 1550
DHLEFWEGVF TGMTHIDAHF LSQTKQGGEN FAYLVAYQAT VCARAKAPPP 1600
SWDTMWKCLI RLKPMLTGPT PLLYRLGAVQ NEIITTHPIT KYIMTCMAAD 1650
LEVITSTWVL AGGIVAALAA YCLTVGSVVI CGRIVTSGKP VPLPDREVLY 1700
RQFDEMEECS RHIPYLAEGQ QIAEQFKQKI LGLLQNTAKQ AEDLKPAVQS 1750
AWPKLEQFWQ KHLWNFVSGV QYLAGLSTLP GNPAVASLMS FSAALTSPLS 1800
TSTTLLLNIL GGWVASQLAP PTASTAFVVS GLAGAAVGSI GLGKVIIDIL 1850
AGYGAGVSGA LVAFKIMSGE APAVEDMVNL LPALLSPGAL VVGVVCAAVL 1900
RRHVGPSEGA TQWMNRLIAF ASRGNHVSPT HYVPETDASR AVTTILSSLT 1950
ITSLLRRLHE WISGDWSAPC SCSWLKDVWD WVCTVLSDFK TWLRAKLVPT 2000
LPGIPFISCQ RGFRGVWRGD GVNYTTCSCG ANITGHVKNG SMKIVGPKMC 2050
SNVWNNRFPI NAITTGPSVP VPEPNYHKAL WRVSAEDYVE VVRVNDHHYI 2100
VGATADNLKC PCQVPAPEFF TEVDGVRLHR FAPPCRPLMR DDITFSVGLS 2150
TYVVGSQLPC EPEPDVVILT SMLTDPDHIT AETAARRLAR GSPPSLASSS 2200
ASQLSAPSLK ATCTTAGKHP DAELIEANLL WRQEVGGNIT RVESENKIIV 2250
LDSFDPLIAE TDDREISVGA ECFNPPRPKF PPALPVWARP DYNPPLLQPW 2300
KAPDYEPPLV HGCALPPKGL PPVPPPRKKR VVQLDEGSAK RALAELAQTS 2350
FPPSTATLSE DSGRETSTLS SDMTPPREEA DRASDDGSYS SMPPLEGEPG 2400
DPDLSSGSWS TVSEDHDSVV CCSMSYSWTG ALITPCAAEE EKLPISPLSN 2450
ALIRHHNLVY STTSRSASLR QKKVTFDRVQ VVDQHYYDVL KEIKTKASGV 2500
SAKLLSVEEA CALTPPHSAR SKFGYGAKEV RGLASKAVNH INSVWEDLLE 2550
DNSTPIPTTI MAKNEVFCVD AQKGGRKPAR LIVYPDLGVR VCEKRALYDV 2600
TQKLPIAVMG AAYGFQYSPK QRVDYLLKMW RSKKTPMGFS YDTRCFDSTV 2650
TERDIRTEED IYQCCQLDPV AKKAITSLTE RLYCGGPMYN SRGQSCGYRR 2700
CRASGVLTTS LGNTLTCYLK AQAACRAAKL KDFDMLVCGD DLVVISESMG 2750
VAEDASALRA FTEAMTRYSA PPGDDPQPEY DLELITSCSS NVSVAHDGAG 2800
QRYYYLTRDP LTPLSRAAWE TARHTPVNSW LGNIIMYAPT IWVRMVLMTH 2850
FFAILQSQEI LHKALDFDMY GVTYSVTPLD LPYIIQRLHG MAAFSLHGYS 2900
PGELNRVASC LRKLGAPPLR AWRHRARAVR AKLIAQGGKH AICGKYLFNW 2950
AVRTKLKLTP LRGAANLDLS GWFVSGGSGG DIFHSVSRAR PRNLLLCLLL 3000
LTVGVGIFLL PAR 3013
Length:3,013
Mass (Da):328,200
Last modified:January 23, 2007 - v3
Checksum:iC9EE9C0231E86EAF
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
D84263 Genomic RNA. Translation: BAA32665.1.

Cross-referencesi

Web resourcesi

euHCVdb

The European HCV database

Virus Pathogen Resource

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
D84263 Genomic RNA. Translation: BAA32665.1 .

3D structure databases

ProteinModelPortali O92530.
SMRi O92530. Positions 16-45, 900-1024, 1027-1655, 1971-2001, 2006-2168, 2423-2985.
ModBasei Search...
MobiDBi Search...

Protein family/group databases

MEROPSi C18.001.
TCDBi 1.A.53.1.6. the hepatitis c virus p7 viroporin cation-selective channel (hcv-p7) family.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Organism-specific databases

euHCVdbi D84263.

Family and domain databases

Gene3Di 3.40.50.300. 2 hits.
InterProi IPR011492. DEAD_Flavivir.
IPR002521. HCV_core_C.
IPR002522. HCV_core_N.
IPR002519. HCV_env.
IPR002531. HCV_NS1.
IPR002518. HCV_NS2.
IPR000745. HCV_NS4a.
IPR001490. HCV_NS4b.
IPR002868. HCV_NS5a.
IPR013193. HCV_NS5a_1B_dom.
IPR024350. HCV_NS5a_C.
IPR014001. Helicase_ATP-bd.
IPR001650. Helicase_C.
IPR013192. NS5A_1a.
IPR027417. P-loop_NTPase.
IPR004109. Peptidase_S29.
IPR007094. RNA-dir_pol_PSvirus.
IPR002166. RNA_pol_HCV.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view ]
Pfami PF07652. Flavi_DEAD. 1 hit.
PF01543. HCV_capsid. 1 hit.
PF01542. HCV_core. 1 hit.
PF01539. HCV_env. 1 hit.
PF01560. HCV_NS1. 1 hit.
PF01538. HCV_NS2. 1 hit.
PF01006. HCV_NS4a. 1 hit.
PF01001. HCV_NS4b. 1 hit.
PF01506. HCV_NS5a. 1 hit.
PF08300. HCV_NS5a_1a. 1 hit.
PF08301. HCV_NS5a_1b. 1 hit.
PF12941. HCV_NS5a_C. 1 hit.
PF02907. Peptidase_S29. 1 hit.
PF00998. RdRP_3. 1 hit.
[Graphical view ]
ProDomi PD001388. HCV_env. 1 hit.
[Graphical view ] [Entries sharing at least one domain ]
SMARTi SM00487. DEXDc. 1 hit.
[Graphical view ]
SUPFAMi SSF50494. SSF50494. 1 hit.
SSF52540. SSF52540. 2 hits.
PROSITEi PS51693. HCV_NS2_PRO. 1 hit.
PS51192. HELICASE_ATP_BIND_1. 1 hit.
PS51194. HELICASE_CTER. 1 hit.
PS50507. RDRP_SSRNA_POS. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "The entire nucleotide sequences of three hepatitis C virus isolates in genetic groups 7-9 and comparison with those in the other eight genetic groups."
    Tokita H., Okamoto H., Iizuka H., Kishimoto J., Tsuda F., Miyakawa Y., Mayumi M.
    J. Gen. Virol. 79:1847-1857(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
  2. "Properties of the hepatitis C virus core protein: a structural protein that modulates cellular processes."
    McLauchlan J.
    J. Viral Hepat. 7:2-14(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  3. Cited for: REVIEW, SUBCELLULAR LOCATION.
  4. "An RNA-binding protein, hnRNP A1, and a scaffold protein, septin 6, facilitate hepatitis C virus replication."
    Kim C.S., Seol S.K., Song O.-K., Park J.H., Jang S.K.
    J. Virol. 81:3852-3865(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HNRNPA1 AND SEPT6.

Entry informationi

Entry nameiPOLG_HCVVN
AccessioniPrimary (citable) accession number: O92530
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 10, 2006
Last sequence update: January 23, 2007
Last modified: May 14, 2014
This is version 115 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Miscellaneousi

Miscellaneous

Cell culture adaptation of the virus leads to mutations in NS5A, reducing its inhibitory effect on replication 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.

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.

Keywords - Technical termi

Complete proteome, Multifunctional enzyme

Documents

  1. Peptidase families
    Classification of peptidase families and list of entries
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi