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Protein

Genome polyprotein

Gene
N/A
Organism
Hepatitis C virus (isolate Glasgow) (HCV)
Status
Reviewed-Annotation score: 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).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).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).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).By similarity

Enzyme regulationi

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

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Ion channel, Protease, Ribonucleoprotein, Thiol protease, Viral ion channel

Keywords - Biological processi

Apoptosis, Clathrin-mediated endocytosis of virus by host, Fusion of virus membrane with host endosomal membrane, Fusion of virus membrane with host membrane, Host-virus interaction, Interferon antiviral system evasion, Ion transport, Transport, Viral attachment to host cell, Viral penetration into host cytoplasm, Virus endocytosis by host, Virus entry into host cell

Keywords - Ligandi

RNA-binding, Viral nucleoprotein, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
Genome polyprotein
Cleaved into the following 6 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
OrganismiHepatitis C virus (isolate Glasgow) (HCV)
Taxonomic identifieri329389 [NCBI]
Taxonomic lineageiVirusesssRNA virusesssRNA positive-strand viruses, no DNA stageFlaviviridaeHepacivirus
Virus hostiHomo sapiens (Human) [TaxID: 9606]

Subcellular locationi

Core protein p21 :
Core protein p19 :
Envelope glycoprotein E1 :
  • Virion membrane Curated; Single-pass type I membrane protein Curated
  • Host endoplasmic reticulum membrane By similarity; 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).By similarity
Envelope glycoprotein E2 :
  • Virion membrane Curated; Single-pass type I membrane protein Curated
  • Host endoplasmic reticulum membrane By similarity; 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).By similarity
p7 :
  • Host endoplasmic reticulum membrane By similarity; 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).By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini2 – 168CytoplasmicSequence analysisAdd BLAST167
Transmembranei169 – 189HelicalSequence analysisAdd BLAST21
Topological domaini190 – 358LumenalSequence analysisAdd BLAST169
Transmembranei359 – 379HelicalSequence analysisAdd BLAST21
Topological domaini380 – 725LumenalSequence analysisAdd BLAST346
Transmembranei726 – 746HelicalSequence analysisAdd BLAST21
Topological domaini747 – 757LumenalSequence analysisAdd BLAST11
Transmembranei758 – 778HelicalSequence analysisAdd BLAST21
Topological domaini779 – 782CytoplasmicSequence analysis4
Transmembranei783 – 803HelicalSequence analysisAdd BLAST21
Topological domaini804 – 813LumenalSequence analysis10
Transmembranei814 – ›829HelicalSequence analysisAdd BLAST›16

GO - Cellular componenti

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

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi180 – 184ALLSC → VLLLV: Complete loss of processing. 1 Publication5

Keywords - Diseasei

Oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved; by hostBy similarity
ChainiPRO_00000375592 – 191Core protein p21Add BLAST190
ChainiPRO_00000375602 – 177Core protein p19By similarityAdd BLAST176
PropeptideiPRO_0000037561178 – 191ER anchor for the core protein, removed in mature form by host signal peptidaseBy similarityAdd BLAST14
ChainiPRO_0000037562192 – 383Envelope glycoprotein E1Sequence analysisAdd BLAST192
ChainiPRO_0000037563384 – 746Envelope glycoprotein E2Sequence analysisAdd BLAST363
ChainiPRO_0000037564747 – 809p7By similarityAdd BLAST63
ChainiPRO_0000037565810 – ›829Protease NS2-3Sequence analysisAdd BLAST›20

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserine; by hostBy similarity1
Modified residuei53Phosphoserine; by hostBy similarity1
Modified residuei99Phosphoserine; by hostBy similarity1
Modified residuei116Phosphoserine; by host PKABy similarity1
Glycosylationi196N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi209N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi234N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi305N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi417N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi423N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi430N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi448N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi540N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi556N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi576N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi623N-linked (GlcNAc...); by hostSequence analysis1
Glycosylationi645N-linked (GlcNAc...); by hostSequence analysis1

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 and NS2-3) are cleaved by the viral proteases (By similarity).By similarity
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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei177 – 178Cleavage; by host signal peptidaseBy similarity2
Sitei191 – 192Cleavage; by host signal peptidaseSequence analysis2
Sitei383 – 384Cleavage; by host signal peptidaseSequence analysis2
Sitei746 – 747Cleavage; by host signal peptidaseBy similarity2
Sitei809 – 810Cleavage; by host signal peptidaseBy similarity2

Keywords - PTMi

Acetylation, Glycoprotein, 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, 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).By similarity

Protein-protein interaction databases

IntActiQ5EG65. 1 interactor.

Structurei

Secondary structure

1829
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi414 – 416Combined sources3
Beta strandi419 – 421Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4GAGX-ray1.80P412-423[»]
ProteinModelPortaliQ5EG65.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 59Interaction with DDX3XBy similarityAdd BLAST58
Regioni2 – 23Interaction with STAT1By similarityAdd BLAST22
Regioni122 – 173Interaction with APOA2By similarityAdd BLAST52
Regioni150 – 159Mitochondrial targeting signalBy similarity10
Regioni164 – 167Important for lipid droplets localizationBy similarity4
Regioni265 – 296Fusion peptideSequence analysisAdd BLAST32
Regioni385 – 411HVR1By similarityAdd BLAST27
Regioni475 – 481HVR2By similarity7
Regioni482 – 494CD81-binding 1Sequence analysisAdd BLAST13
Regioni522 – 553CD81-binding 2Sequence analysisAdd BLAST32
Regioni660 – 671PKR/eIF2-alpha phosphorylation homology domain (PePHD)Add BLAST12

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi5 – 13Nuclear localization signalSequence analysis9
Motifi38 – 43Nuclear localization signalSequence analysis6
Motifi58 – 64Nuclear localization signalSequence analysis7
Motifi66 – 71Nuclear localization signalSequence analysis6

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi476 – 479Poly-Gly4
Compositional biasi796 – 803Poly-Leu8

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 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).By similarity

Sequence similaritiesi

Belongs to the hepacivirus polyprotein family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Family and domain databases

InterProiIPR002521. HCV_core_C.
IPR002522. HCV_core_N.
IPR002519. HCV_env.
IPR002531. HCV_NS1.
[Graphical view]
PfamiPF01543. HCV_capsid. 1 hit.
PF01542. HCV_core. 1 hit.
PF01539. HCV_env. 1 hit.
PF01560. HCV_NS1. 1 hit.
[Graphical view]
ProDomiPD001388. HCV_env. 1 hit.
[Graphical view] [Entries sharing at least one domain]

Sequencei

Sequence statusi: Fragment.

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

Q5EG65-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSTNPKPQRK TKRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRATR
60 70 80 90 100
KTSERSQPRG RRQPIPKARR PKGRNWAQPG YPWPLYGNEG CGWAGWLPSP
110 120 130 140 150
RGSRPSWGPN DPRRRSRNLG KVIDTLTCGF VDLMGYIPLV GAPLRGAARA
160 170 180 190 200
LAHGVRVLED GVNYATGNLP GCSFSIFLLA LLSCLTVPAS AYQVRNSTGL
210 220 230 240 250
YHVTNDCPNS SIVYEAVDAI LHTPGCVPCV REGNASRCWV AMTPTVATRD
260 270 280 290 300
GRLPTTQLRR HIDLLVGSAT LCSALYVGDL CGSVFLVGQL FTFSPRRHWT
310 320 330 340 350
TQGCNCSIYP GHITGHRMAW DMMMNWSPTT ALVVAQLLRI PQAILDMIAG
360 370 380 390 400
AHWGVLAGMA YFSMVGNWAK VLAVLLLFAG VDAETHVTGG AAARSTLQLA
410 420 430 440 450
GLFQPGAKQN VQLINTNGSW HVNRTALNCN DSLNTGWIAG LFYYHGFNSS
460 470 480 490 500
GCSERLASCR SLTDFDQGWG PISYAGGGGP DHRPYCWHYP PKPCGIVPAK
510 520 530 540 550
SVCGPVYCFT PSPVVVGTTD RSGAPTYSWG ADDTDVFVLN NTRPPLGNWF
560 570 580 590 600
GCTWMNSTGF TKVCGAPPCV IGGVGNNTLH CPTDCFRKHP EATYSRCGSG
610 620 630 640 650
PWLTPRCLVD YPYRLWHYPC TINHSIFKVR MYVGGVEHRL DAACNWTRGE
660 670 680 690 700
RCDLEDRDRS ELSPLLLSTT QWQVLPCSFT TLPALSTGLI HLHQNIVDVQ
710 720 730 740 750
YLYGVGSSIA SWAIKWEYVV LLFLLLADAR VCSCLWMMLL ISQAEAALEN
760 770 780 790 800
LVVLNAASLA GTHGLVSFLV FFCFAWFLRG KWVPGAVYAL YGMWPLLLLL
810 820
LALPQRAYAL DTEVAASCGG VVLVGLMAL
Length:829
Mass (Da):90,587
Last modified:January 23, 2007 - v3
Checksum:i17AD3868F50B4AD4
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Non-terminal residuei8291

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY885238 Genomic RNA. Translation: AAW78019.1.

Cross-referencesi

Web resourcesi

euHCVdb

The European HCV database

Virus Pathogen Resource

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY885238 Genomic RNA. Translation: AAW78019.1.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4GAGX-ray1.80P412-423[»]
ProteinModelPortaliQ5EG65.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ5EG65. 1 interactor.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Organism-specific databases

euHCVdbiAY885238.

Family and domain databases

InterProiIPR002521. HCV_core_C.
IPR002522. HCV_core_N.
IPR002519. HCV_env.
IPR002531. HCV_NS1.
[Graphical view]
PfamiPF01543. HCV_capsid. 1 hit.
PF01542. HCV_core. 1 hit.
PF01539. HCV_env. 1 hit.
PF01560. HCV_NS1. 1 hit.
[Graphical view]
ProDomiPD001388. HCV_env. 1 hit.
[Graphical view] [Entries sharing at least one domain]
ProtoNetiSearch...

Entry informationi

Entry nameiPOLG_HCVGL
AccessioniPrimary (citable) accession number: Q5EG65
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 19, 2005
Last sequence update: January 23, 2007
Last modified: November 30, 2016
This is version 97 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Miscellaneousi

Miscellaneous

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.Curated

Keywords - Technical termi

3D-structure

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.