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P26661

- POLG_HCVJ8

UniProt

P26661 - POLG_HCVJ8

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Protein
Genome polyprotein
Gene
N/A
Organism
Hepatitis C virus genotype 2b (isolate HC-J8) (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
Sitei750 – 7512Cleavage; by host signal peptidase By similarity
Sitei813 – 8142Cleavage; by host signal peptidase By similarity
Active sitei956 – 9561For protease NS2-3 activity; shared with dimeric partner By similarity
Active sitei976 – 9761For protease NS2-3 activity; shared with dimeric partner By similarity
Active sitei997 – 9971For protease NS2-3 activity; shared with dimeric partner By similarity
Sitei1030 – 10312Cleavage; by protease NS2-3 Reviewed prediction
Active sitei1087 – 10871Charge relay system; for serine protease NS3 activity By similarity
Active sitei1111 – 11111Charge relay system; for serine protease NS3 activity By similarity
Metal bindingi1127 – 11271Zinc By similarity
Metal bindingi1129 – 11291Zinc By similarity
Active sitei1169 – 11691Charge relay system; for serine protease NS3 activity By similarity
Metal bindingi1175 – 11751Zinc By similarity
Metal bindingi1179 – 11791Zinc By similarity
Sitei1661 – 16622Cleavage; by serine protease NS3 Reviewed prediction
Sitei1715 – 17162Cleavage; by serine protease NS3 Reviewed prediction
Sitei1976 – 19772Cleavage; by serine protease NS3 Reviewed prediction
Metal bindingi2015 – 20151Zinc By similarity
Metal bindingi2033 – 20331Zinc By similarity
Metal bindingi2035 – 20351Zinc By similarity
Metal bindingi2056 – 20561Zinc By similarity
Sitei2442 – 24432Cleavage; by serine protease NS3 Reviewed prediction

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi1234 – 12418ATP Reviewed prediction

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. ATP-dependent helicase activity Source: InterPro
  3. RNA binding Source: UniProtKB-KW
  4. RNA-directed RNA polymerase activity Source: UniProtKB-KW
  5. cysteine-type endopeptidase activity Source: InterPro
  6. ion channel 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

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 2b (isolate HC-J8) (HCV)
Taxonomic identifieri11115 [NCBI]
Taxonomic lineageiVirusesssRNA positive-strand viruses, no DNA stageFlaviviridaeHepacivirus
Virus hostiHomo sapiens (Human) [TaxID: 9606]
ProteomesiUP000002680: 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 prediction
Add
BLAST
Transmembranei169 – 18921Helical; Reviewed prediction
Add
BLAST
Topological domaini190 – 358169Lumenal Reviewed prediction
Add
BLAST
Transmembranei359 – 37921Helical; Reviewed prediction
Add
BLAST
Topological domaini380 – 729350Lumenal Reviewed prediction
Add
BLAST
Transmembranei730 – 75021Helical; Reviewed prediction
Add
BLAST
Topological domaini751 – 76111Lumenal Reviewed prediction
Add
BLAST
Transmembranei762 – 78221Helical; Reviewed prediction
Add
BLAST
Topological domaini783 – 7864Cytoplasmic Reviewed prediction
Transmembranei787 – 80721Helical; Reviewed prediction
Add
BLAST
Topological domaini808 – 81710Lumenal Reviewed prediction
Transmembranei818 – 83821Helical; Reviewed prediction
Add
BLAST
Topological domaini839 – 88547Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei886 – 90621Helical; Reviewed prediction
Add
BLAST
Topological domaini907 – 93226Lumenal Reviewed prediction
Add
BLAST
Transmembranei933 – 95321Helical; Reviewed prediction
Add
BLAST
Topological domaini954 – 1661708Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei1662 – 168221Helical; Reviewed prediction
Add
BLAST
Topological domaini1683 – 1809127Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei1810 – 183021Helical; Reviewed prediction
Add
BLAST
Topological domaini1831 – 18322Lumenal Reviewed prediction
Transmembranei1833 – 185321Helical; Reviewed prediction
Add
BLAST
Topological domaini1854 – 18541Cytoplasmic Reviewed prediction
Transmembranei1855 – 187521Helical; Reviewed prediction
Add
BLAST
Topological domaini1876 – 188510Lumenal Reviewed prediction
Transmembranei1886 – 190621Helical; Reviewed prediction
Add
BLAST
Topological domaini1907 – 197670Cytoplasmic Reviewed prediction
Add
BLAST
Intramembranei1977 – 200630 By similarity
Add
BLAST
Topological domaini2007 – 30121006Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei3013 – 303321Helical; By similarity
Add
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 prediction
PRO_0000037625Add
BLAST
Chaini2 – 177176Core protein p19 By similarity
PRO_0000037626Add
BLAST
Propeptidei178 – 19114ER anchor for the core protein, removed in mature form by host signal peptidase By similarity
PRO_0000037627Add
BLAST
Chaini192 – 383192Envelope glycoprotein E1 Reviewed prediction
PRO_0000037628Add
BLAST
Chaini384 – 750367Envelope glycoprotein E2 Reviewed prediction
PRO_0000037629Add
BLAST
Chaini751 – 81363p7 By similarity
PRO_0000037630Add
BLAST
Chaini814 – 1030217Protease NS2-3 Reviewed prediction
PRO_0000037631Add
BLAST
Chaini1031 – 1661631Serine protease NS3 Reviewed prediction
PRO_0000037632Add
BLAST
Chaini1662 – 171554Non-structural protein 4A Reviewed prediction
PRO_0000037633Add
BLAST
Chaini1716 – 1976261Non-structural protein 4B Reviewed prediction
PRO_0000037634Add
BLAST
Chaini1977 – 2442466Non-structural protein 5A Reviewed prediction
PRO_0000037635Add
BLAST
Chaini2443 – 3033591RNA-directed RNA polymerase Reviewed prediction
PRO_0000037636Add
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
Glycosylationi233 – 2331N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi299 – 2991N-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
Glycosylationi477 – 4771N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi534 – 5341N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi542 – 5421N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi558 – 5581N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi578 – 5781N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi627 – 6271N-linked (GlcNAc...); by host Reviewed prediction
Glycosylationi649 – 6491N-linked (GlcNAc...); by host Reviewed prediction
Lipidationi1972 – 19721S-palmitoyl cysteine; by host By similarity
Lipidationi1976 – 19761S-palmitoyl cysteine; by host By similarity
Disulfide bondi2118 ↔ 2166 By similarity
Modified residuei2198 – 21981Phosphoserine; by host; in p56 By similarity
Modified residuei2201 – 22011Phosphoserine; by host; in p58 By similarity
Modified residuei2205 – 22051Phosphoserine; by host; in p58 By similarity
Modified residuei2208 – 22081Phosphoserine; 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

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi18 – 203
Beta strandi23 – 253
Turni33 – 353
Beta strandi2444 – 24485
Helixi2467 – 24704
Helixi2476 – 24783
Beta strandi2479 – 24813
Helixi2484 – 24863
Helixi2487 – 24948
Helixi2504 – 251714
Helixi2527 – 25326
Beta strandi2542 – 25443
Helixi2547 – 25515
Helixi2555 – 257016
Beta strandi2572 – 25743
Beta strandi2578 – 25825
Beta strandi2586 – 25883
Beta strandi2601 – 26055
Helixi2607 – 262923
Helixi2630 – 26323
Helixi2634 – 26363
Helixi2639 – 265113
Beta strandi2653 – 26619
Helixi2666 – 26694
Helixi2672 – 268413
Helixi2689 – 270113
Turni2702 – 27043
Beta strandi2706 – 27094
Beta strandi2715 – 27195
Helixi2729 – 274820
Beta strandi2754 – 27585
Beta strandi2761 – 27677
Helixi2771 – 278717
Beta strandi2792 – 27943
Helixi2802 – 28043
Beta strandi2810 – 28167
Beta strandi2822 – 28287
Helixi2831 – 284212
Helixi2849 – 28579
Helixi2861 – 28655
Helixi2867 – 287812
Beta strandi2885 – 28895
Beta strandi2892 – 28965
Helixi2898 – 29003
Helixi2901 – 29099
Helixi2911 – 29144
Helixi2921 – 293414
Helixi2939 – 295618
Helixi2958 – 296710
Helixi2969 – 29713
Helixi2984 – 29863
Helixi2990 – 29923
Helixi2998 – 30003

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1XCQX-ray3.50P/Q/S2-45[»]
1XCTX-ray3.05P/Q2-45[»]
1XF5X-ray2.60P/Q2-45[»]
3GSZX-ray1.90A/B2443-3005[»]
3HVOX-ray2.00A/B2443-3005[»]
ProteinModelPortaliP26661.
SMRiP26661. Positions 2-45, 906-1030, 1033-1661, 1977-2007, 2012-2174, 2443-2990.

Miscellaneous databases

EvolutionaryTraceiP26661.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini907 – 1030124Peptidase C18
Add
BLAST
Domaini1221 – 1373153Helicase ATP-binding
Add
BLAST
Domaini2656 – 2774119RdRp catalytic
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni2 – 5958Interaction with DDX3X By similarity
Add
BLAST
Regioni2 – 2322Interaction with STAT1 By similarity
Add
BLAST
Regioni122 – 17352Interaction with APOA2 By similarity
Add
BLAST
Regioni150 – 15910Mitochondrial targeting signal By similarity
Regioni164 – 1674Important for lipid droplets localization By similarity
Regioni265 – 29632Fusion peptide Reviewed prediction
Add
BLAST
Regioni385 – 41127HVR1 By similarity
Add
BLAST
Regioni484 – 49613CD81-binding 1 Reviewed prediction
Add
BLAST
Regioni524 – 55532CD81-binding 2 Reviewed prediction
Add
BLAST
Regioni664 – 67512PKR/eIF2-alpha phosphorylation homology domain (PePHD) By similarity
Add
BLAST
Regioni1683 – 169412NS3-binding (by NS4A) Reviewed prediction
Add
BLAST
Regioni2124 – 2332209Transcriptional activation Reviewed prediction
Add
BLAST
Regioni2124 – 221289FKBP8-binding Reviewed prediction
Add
BLAST
Regioni2204 – 225047Basal phosphorylation By similarity
Add
BLAST
Regioni2214 – 227562PKR-binding Reviewed prediction
Add
BLAST
Regioni2249 – 230658NS4B-binding Reviewed prediction
Add
BLAST
Regioni2351 – 244292Basal phosphorylation By similarity
Add
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
Motifi1320 – 13234DECH box By similarity
Motifi2322 – 23254SH3-binding Reviewed prediction
Motifi2327 – 23359Nuclear localization signal Reviewed prediction

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi1436 – 14394Poly-Val
Compositional biasi2282 – 232746Pro-rich
Add
BLAST
Compositional biasi2328 – 23314Poly-Arg
Compositional biasi3013 – 30219Poly-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.
PS50507. RDRP_SSRNA_POS. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

P26661-1 [UniParc]FASTAAdd to Basket

« Hide

MSTNPKPQRK TKRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRATR     50
KTSERSQPRG RRQPIPKDRR STGKSWGKPG YPWPLYGNEG CGWAGWLLSP 100
RGSRPTWGPT DPRHRSRNLG RVIDTITCGF ADLMGYIPVV GAPVGGVARA 150
LAHGVRVLED GINYATGNLP GCSFSIFLLA LLSCVTVPVS AVEVRNISSS 200
YYATNDCSNN SITWQLTDAV LHLPGCVPCE NDNGTLHCWI QVTPNVAVKH 250
RGALTRSLRT HVDMIVMAAT ACSALYVGDV CGAVMILSQA FMVSPQRHNF 300
TQECNCSIYQ GHITGHRMAW DMMLSWSPTL TMILAYAARV PELVLEIIFG 350
GHWGVVFGLA YFSMQGAWAK VIAILLLVAG VDATTYSSGQ EAGRTVAGFA 400
GLFTTGAKQN LYLINTNGSW HINRTALNCN DSLQTGFLAS LFYTHKFNSS 450
GCPERLSSCR GLDDFRIGWG TLEYETNVTN DGDMRPYCWH YPPRPCGIVP 500
ARTVCGPVYC FTPSPVVVGT TDKQGVPTYT WGENETDVFL LNSTRPPRGA 550
WFGCTWMNGT GFTKTCGAPP CRIRKDYNST IDLLCPTDCF RKHPDATYLK 600
CGAGPWLTPR CLVDYPYRLW HYPCTVNFTI FKARMYVGGV EHRFSAACNF 650
TRGDRCRLED RDRGQQSPLL HSTTEWAVLP CSFSDLPALS TGLLHLHQNI 700
VDVQYLYGLS PALTRYIVKW EWVILLFLLL ADARICACLW MLIILGQAEA 750
ALEKLIILHS ASAASANGPL WFFIFFTAAW YLKGRVVPVA TYSVLGLWSF 800
LLLVLALPQQ AYALDAAEQG ELGLAILVII SIFTLTPAYK ILLSRSVWWL 850
SYMLVLAEAQ IQQWVPPLEV RGGRDGIIWV AVILHPRLVF EVTKWLLAIL 900
GPAYLLKASL LRIPYFVRAH ALLRVCTLVK HLAGARYIQM LLITIGRWTG 950
TYIYDHLSPL STWAAQGLRD LAIAVEPVVF SPMEKKVIVW GAETVACGDI 1000
LHGLPVSARL GREVLLGPAD GYTSKGWKLL APITAYTQQT RGLLGAIVVS 1050
LTGRDKNEQA GQVQVLSSVT QTFLGTSISG VLWTVYHGAG NKTLAGPKGP 1100
VTQMYTSAEG DLVGWPSPPG TKSLDPCTCG AVDLYLVTRN ADVIPVRRKD 1150
DRRGALLSPR PLSTLKGSSG GPVLCSRGHA VGLFRAAVCA RGVAKSIDFI 1200
PVESLDVATR TPSFSDNSTP PAVPQSYQVG YLHAPTGSGK STKVPAAYAS 1250
QGYKVLVLNP SVAATLGFGA YMSKAHGINP NIRTGVRTVT TGDSITYSTY 1300
GKFIADGGCA AGAYDIIICD ECHSVDATTI LGIGTVLDQA ETAGVRLVVL 1350
ATATPPGTVT TPHSNIEEVA LGHEGEIPFY GKAIPLAFIK GGRHLIFCHS 1400
KKKCDELAAA LRGMGVNAVA YYRGLDVSVI PTQGDVVVVA TDALMTGYTG 1450
DFDSVIDCNV AVSQIVDFSL DPTFTITTQT VPQDAVSRSQ RRGRTGRGRL 1500
GVYRYVSSGE RPSGMFDSVV LCECYDAGAA WYELTPAETT VRLRAYFNTP 1550
GLPVCQDHLE FWEAVFTGLT HIDAHFLSQT KQGGENFAYL TAYQATVCAR 1600
AKAPPPSWDV MWKCLTRLKP TLTGPTPLLY RLGAVTNEVT LTHPVTKYIA 1650
TCMQADLEIM TSSWVLAGGV LAAVAAYCLA TGCISIIGRL HLNDRVVVAP 1700
DKEILYEAFD EMEECASKAA LIEEGQRMAE MLKSKIQGLL QQATRQAQDI 1750
QPAIQSSWPK LEQFWAKHMW NFISGIQYLA GLSTLPGNPA VASMMAFSAA 1800
LTSPLPTSTT ILLNIMGGWL ASQIAPPAGA TGFVVSGLVG AAVGSIGLGK 1850
ILVDVLAGYG AGISGALVAF KIMSGEKPTV EDVVNLLPAI LSPGALVVGV 1900
ICAAILRRHV GQGEGAVQWM NRLIAFASRG NHVAPTHYVV ESDASQRVTQ 1950
VLSSLTITSL LRRLHAWITE DCPVPCSGSW LQDIWDWVCS ILTDFKNWLS 2000
SKLLPKMPGI PFISCQKGYK GVWAGTGVMT TRCPCGANIS GHVRMGTMKI 2050
TGPKTCLNLW QGTFPINCYT EGPCVPKPPP NYKTAIWRVA ASEYVEVTQH 2100
GSFSYVTGLT SDNLKVPCQV PAPEFFSWVD GVQIHRFAPV PGPFFRDEVT 2150
FTVGLNSFVV GSQLPCDPEP DTEVLASMLT DPSHITAEAA ARRLARGSPP 2200
SQASSSASQL SAPSLKATCT THKTAYDCDM VDANLFMGGD VTRIESDSKV 2250
IVLDSLDSMT EVEDDREPSV PSEYLIKRRK FPPALPPWAR PDYNPVLIET 2300
WKRPGYEPPT VLGCALPPTP QTPVPPPRRR RAKVLTQDNV EGVLREMADK 2350
VLSPLQDNND SGHSTGADTG GDIVQQPSDE TAASEAGSLS SMPPLEGEPG 2400
DPDLEFEPVG SAPPSEGECE VIDSDSKSWS TVSDQEDSVI CCSMSYSWTG 2450
ALITPCGPEE EKLPINPLSN SLMRFHNKVY STTSRSASLR AKKVTFDRVQ 2500
VLDAHYDSVL QDVKRAASKV SARLLTVEEA CALTPPHSAK SRYGFGAKEV 2550
RSLSRRAVNH IRSVWEDLLE DQHTPIDTTI MAKNEVFCID PTKGGKKPAR 2600
LIVYPDLGVR VCEKMALYDI AQKLPKAIMG PSYGFQYSPA ERVDFLLKAW 2650
GSKKDPMGFS YDTRCFDSTV TERDIRTEES IYQACSLPQE ARTVIHSLTE 2700
RLYVGGPMTN SKGQSCGYRR CRASGVFTTS MGNTMTCYIK ALAACKAAGI 2750
VDPVMLVCGD DLVVISESQG NEEDERNLRA FTEAMTRYSA PPGDLPRPEY 2800
DLELITSCSS NVSVALDSRG RRRYFLTRDP TTPITRAAWE TVRHSPVNSW 2850
LGNIIQYAPT IWVRMVIMTH FFSILLAQDT LNQNLNFEMY GAVYSVNPLD 2900
LPAIIERLHG LEAFSLHTYS PHELSRVAAT LRKLGAPPLR AWKSRARAVR 2950
ASLIAQGARA AICGRYLFNW AVKTKLKLTP LPEASRLDLS GWFTVGAGGG 3000
DIYHSVSHAR PRLLLLCLLL LSVGVGIFLL PAR 3033
Length:3,033
Mass (Da):330,182
Last modified:January 23, 2007 - v3
Checksum:i1A173E7E3381FD1A
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
D10988 Genomic RNA. Translation: BAA01761.1.
PIRiA40250. GNWVJ8.

Cross-referencesi

Web resourcesi

euHCVdb

The European HCV database

Virus Pathogen Resource

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
D10988 Genomic RNA. Translation: BAA01761.1 .
PIRi A40250. GNWVJ8.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1XCQ X-ray 3.50 P/Q/S 2-45 [» ]
1XCT X-ray 3.05 P/Q 2-45 [» ]
1XF5 X-ray 2.60 P/Q 2-45 [» ]
3GSZ X-ray 1.90 A/B 2443-3005 [» ]
3HVO X-ray 2.00 A/B 2443-3005 [» ]
ProteinModelPortali P26661.
SMRi P26661. Positions 2-45, 906-1030, 1033-1661, 1977-2007, 2012-2174, 2443-2990.
ModBasei Search...
MobiDBi Search...

Protocols and materials databases

Structural Biology Knowledgebase Search...

Organism-specific databases

euHCVdbi D10988.

Miscellaneous databases

EvolutionaryTracei P26661.

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.
PS50507. RDRP_SSRNA_POS. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Full-length sequence of a hepatitis C virus genome having poor homology to reported isolates: comparative study of four distinct genotypes."
    Okamoto H., Kurai K., Okada S., Yamamoto K., Lizuka H., Tanaka T., Fukuda S., Tsuda F., Mishiro S.
    Virology 188:331-341(1992) [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_HCVJ8
AccessioniPrimary (citable) accession number: P26661
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1992
Last sequence update: January 23, 2007
Last modified: July 9, 2014
This is version 144 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

3D-structure, Complete proteome, Multifunctional enzyme

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. Peptidase families
    Classification of peptidase families and list of entries
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi