Q5EG65 (POLG_HCVGL) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names	Recommended name: Genome polyprotein Cleaved into the following 6 chains: Core protein p21 Alternative name(s): Capsid protein C p21 Core protein p19 Envelope glycoprotein E1 Alternative name(s): gp32 gp35 Envelope glycoprotein E2 Alternative name(s): NS1 gp68 gp70 p7 Protease NS2-3 Short name=p23 EC=3.4.22.-
Organism	Hepatitis C virus (isolate Glasgow) (HCV)
Taxonomic identifier	329389 [NCBI]
Taxonomic lineage	Viruses › ssRNA viruses › ssRNA positive-strand viruses, no DNA stage › Flaviviridae › Hepacivirus › Hepatitis C virus › unclassified Hepatitis C virus
Virus host	Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	829 AA.
Sequence status	Fragment.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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.
Enzyme regulation	Activity of auto-protease NS2-3 is dependent on zinc ions and completely inhibited by EDTA By similarity.
Subunit structure	Core protein is a homomultimer that binds the C-terminal part of E1 and interacts with numerous cellular proteins. Interaction with human STAT1 SH2 domain seems to result in decreased STAT1 phosphorylation, leading to decreased IFN-stimulated gene transcription. In addition to blocking the formation of phosphorylated STAT1, the core protein also promotes ubiquitin-mediated proteasome-dependent degradation of STAT1. Interacts with, and constitutively activates human STAT3. Associates with human LTBR and TNFRSF1A receptors and possibly induces apoptosis. Binds to human SP110 isoform 3/Sp110b, HNRPK, C1QR1, YWHAE, UBE3A/E6AP, DDX3X, APOA2 and RXRA proteins. Interacts with human CREB3 nuclear transcription protein, triggering cell transformation. May interact with human p53. Also binds human cytokeratins KRT8, KRT18, KRT19 and VIM (vimentin). E1 and E2 glycoproteins form a heterodimer that binds to human LDLR, CD81 and SCARB1 receptors. E2 binds and inhibits human EIF2AK2/PKR. Also binds human CD209/DC-SIGN and CLEC4M/DC-SIGNR. p7 forms a homoheptamer in vitro By similarity. Ref.2
Subcellular location	Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein By similarity. Host mitochondrion membrane; Single-pass type I membrane protein By similarity. Host lipid droplet By similarity. Note: The C-terminal transmembrane domain of core protein p21 contains an ER signal leading the nascent polyprotein to the ER membrane. Only a minor proportion of core protein is present in the nucleus and an unknown proportion is secreted By similarity. Ref.3 Ref.5 Core protein p19: Virion By similarity. Host cytoplasm By similarity. Host nucleus By similarity. Secreted By similarity Ref.3 Ref.5. Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein Potential. Host endoplasmic reticulum membrane; Single-pass type I membrane protein By similarity. Note: The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase. After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain. These events explain the final topology of the protein. ER retention of E1 is leaky and, in overexpression conditions, only a small fraction reaches the plasma membrane By similarity. Ref.3 Ref.5 Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein Potential. Host endoplasmic reticulum membrane; Single-pass type I membrane protein By similarity. Note: The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase. After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain. These events explain the final topology of the protein. ER retention of E2 is leaky and, in overexpression conditions, only a small fraction reaches the plasma membrane By similarity. Ref.3 Ref.5 p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein By similarity. Host cell membrane By similarity. Note: The C-terminus of p7 membrane domain acts as a signal sequence. After cleavage by host signal peptidase, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. Only a fraction localizes to the plasma membrane By similarity. Ref.3 Ref.5
Domain	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.
Post-translational modification	Specific enzymatic cleavages in vivo yield mature proteins. The structural proteins, core, E1, E2 and p7 are produced by proteolytic processing by host signal peptidases. The core protein is synthesized as a 21 kDa precursor which is retained in the ER membrane through the hydrophobic signal peptide. Cleavage by the signal peptidase releases the 19 kDa mature core protein. The other proteins (p7 and NS2-3) are cleaved by the viral proteases By similarity. Ref.3 Envelope E1 and E2 glycoproteins are highly N-glycosylated By similarity. Core protein is phosphorylated by host PKC and PKA By similarity. Core protein is ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation By similarity.
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.
Sequence similarities	Belongs to the hepacivirus polyprotein family.
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.

Ontologies

Keywords
Biological process	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
Cellular component	Host cell membrane Host cytoplasm Host endoplasmic reticulum Host lipid droplet Host membrane Host mitochondrion Host nucleus Membrane Secreted Viral envelope protein Virion
Disease	Oncogene
Domain	Transmembrane Transmembrane helix
Ligand	RNA-binding Viral nucleoprotein Zinc
Molecular function	Capsid protein Hydrolase Ion channel Protease Ribonucleoprotein Thiol protease Viral ion channel
PTM	Acetylation Glycoprotein Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW evasion or tolerance by virus of host immune response Inferred from electronic annotation. Source: UniProtKB-KW ion transport Inferred from electronic annotation. Source: UniProtKB-KW proteolysis Inferred from electronic annotation. Source: UniProtKB-KW viral attachment to host cell Inferred from electronic annotation. Source: UniProtKB-KW viral entry into host cell via clathrin-mediated endocytosis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	host cell endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell host cell lipid particle Inferred from electronic annotation. Source: UniProtKB-SubCell host cell mitochondrial membrane Inferred from electronic annotation. Source: UniProtKB-SubCell host cell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell host cell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW ribonucleoprotein complex Inferred from electronic annotation. Source: UniProtKB-KW viral capsid Inferred from electronic annotation. Source: UniProtKB-KW viral envelope Inferred from electronic annotation. Source: UniProtKB-KW virion membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	RNA binding Inferred from electronic annotation. Source: UniProtKB-KW cysteine-type peptidase activity Inferred from electronic annotation. Source: UniProtKB-KW structural molecule activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed; by host By similarity

Chain

2 – 191

190

Core protein p21

PRO_0000037559

Chain

2 – 177

176

Core protein p19 By similarity

PRO_0000037560

Propeptide

178 – 191

14

ER anchor for the core protein, removed in mature form by host signal peptidase By similarity

PRO_0000037561

Chain

192 – 383

192

Envelope glycoprotein E1 Potential

PRO_0000037562

Chain

384 – 746

363

Envelope glycoprotein E2 Potential

PRO_0000037563

Chain

747 – 809

63

p7 By similarity

PRO_0000037564

Chain

810 – ›829

›20

Protease NS2-3 Potential

PRO_0000037565

Regions

Topological domain

2 – 168

167

Cytoplasmic Potential

Transmembrane

169 – 189

21

Helical; Potential

Topological domain

190 – 358

169

Lumenal Potential

Transmembrane

359 – 379

21

Helical; Potential

Topological domain

380 – 725

346

Lumenal Potential

Transmembrane

726 – 746

21

Helical; Potential

Topological domain

747 – 757

11

Lumenal Potential

Transmembrane

758 – 778

21

Helical; Potential

Topological domain

779 – 782

4

Cytoplasmic Potential

Transmembrane

783 – 803

21

Helical; Potential

Topological domain

804 – 813

10

Lumenal Potential

Transmembrane

814 – ›829

›16

Helical; Potential

Region

2 – 59

58

Interaction with DDX3X By similarity

Region

2 – 23

22

Interaction with STAT1 By similarity

Region

122 – 173

52

Interaction with APOA2 By similarity

Region

150 – 159

10

Mitochondrial targeting signal By similarity

Region

164 – 167

4

Important for lipid droplets localization By similarity

Region

265 – 296

32

Fusion peptide Potential

Region

385 – 411

27

HVR1 By similarity

Region

475 – 481

7

HVR2 By similarity

Region

482 – 494

13

CD81-binding 1 Potential

Region

522 – 553

32

CD81-binding 2 Potential

Region

660 – 671

12

PKR/eIF2-alpha phosphorylation homology domain (PePHD)

Motif

5 – 13

9

Nuclear localization signal Potential

Motif

38 – 43

6

Nuclear localization signal Potential

Motif

58 – 64

7

Nuclear localization signal Potential

Motif

66 – 71

6

Nuclear localization signal Potential

Compositional bias

476 – 479

4

Poly-Gly

Compositional bias

796 – 803

8

Poly-Leu

Sites

Site

177 – 178

2

Cleavage; by host signal peptidase By similarity

Site

191 – 192

2

Cleavage; by host signal peptidase Potential

Site

383 – 384

2

Cleavage; by host signal peptidase Potential

Site

746 – 747

2

Cleavage; by host signal peptidase By similarity

Site

809 – 810

2

Cleavage; by host signal peptidase By similarity

Amino acid modifications

Modified residue

2

1

N-acetylserine; by host By similarity

Modified residue

53

1

Phosphoserine; by host By similarity

Modified residue

99

1

Phosphoserine; by host By similarity

Modified residue

116

1

Phosphoserine; by host PKA By similarity

Glycosylation

196

1

N-linked (GlcNAc...); by host Potential

Glycosylation

209

1

N-linked (GlcNAc...); by host Potential

Glycosylation

234

1

N-linked (GlcNAc...); by host Potential

Glycosylation

305

1

N-linked (GlcNAc...); by host Potential

Glycosylation

417

1

N-linked (GlcNAc...); by host Potential

Glycosylation

423

1

N-linked (GlcNAc...); by host Potential

Glycosylation

430

1

N-linked (GlcNAc...); by host Potential

Glycosylation

448

1

N-linked (GlcNAc...); by host Potential

Glycosylation

540

1

N-linked (GlcNAc...); by host Potential

Glycosylation

556

1

N-linked (GlcNAc...); by host Potential

Glycosylation

576

1

N-linked (GlcNAc...); by host Potential

Glycosylation

623

1

N-linked (GlcNAc...); by host Potential

Glycosylation

645

1

N-linked (GlcNAc...); by host Potential

Experimental info

Mutagenesis

180 – 184

5

ALLSC → VLLLV: Complete loss of processing. Ref.3

Non-terminal residue

829

1

Secondary structure

1

.

.

.

.

.

829

Helix Strand Turn

Details...

Beta strand

414 – 416

3

Beta strand

419 – 421

3

Sequences

	Sequence		Length	Mass (Da)
	Q5EG65 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 17AD3868F50B4AD4	FASTA	829	90,587
	10 20 30 40 50 60 MSTNPKPQRK TKRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRATR KTSERSQPRG 70 80 90 100 110 120 RRQPIPKARR PKGRNWAQPG YPWPLYGNEG CGWAGWLPSP RGSRPSWGPN DPRRRSRNLG 130 140 150 160 170 180 KVIDTLTCGF VDLMGYIPLV GAPLRGAARA LAHGVRVLED GVNYATGNLP GCSFSIFLLA 190 200 210 220 230 240 LLSCLTVPAS AYQVRNSTGL YHVTNDCPNS SIVYEAVDAI LHTPGCVPCV REGNASRCWV 250 260 270 280 290 300 AMTPTVATRD GRLPTTQLRR HIDLLVGSAT LCSALYVGDL CGSVFLVGQL FTFSPRRHWT 310 320 330 340 350 360 TQGCNCSIYP GHITGHRMAW DMMMNWSPTT ALVVAQLLRI PQAILDMIAG AHWGVLAGMA 370 380 390 400 410 420 YFSMVGNWAK VLAVLLLFAG VDAETHVTGG AAARSTLQLA GLFQPGAKQN VQLINTNGSW 430 440 450 460 470 480 HVNRTALNCN DSLNTGWIAG LFYYHGFNSS GCSERLASCR SLTDFDQGWG PISYAGGGGP 490 500 510 520 530 540 DHRPYCWHYP PKPCGIVPAK SVCGPVYCFT PSPVVVGTTD RSGAPTYSWG ADDTDVFVLN 550 560 570 580 590 600 NTRPPLGNWF GCTWMNSTGF TKVCGAPPCV IGGVGNNTLH CPTDCFRKHP EATYSRCGSG 610 620 630 640 650 660 PWLTPRCLVD YPYRLWHYPC TINHSIFKVR MYVGGVEHRL DAACNWTRGE RCDLEDRDRS 670 680 690 700 710 720 ELSPLLLSTT QWQVLPCSFT TLPALSTGLI HLHQNIVDVQ YLYGVGSSIA SWAIKWEYVV 730 740 750 760 770 780 LLFLLLADAR VCSCLWMMLL ISQAEAALEN LVVLNAASLA GTHGLVSFLV FFCFAWFLRG 790 800 810 820 KWVPGAVYAL YGMWPLLLLL LALPQRAYAL DTEVAASCGG VVLVGLMAL

References

[1]	"Covalent interactions are not required to permit or stabilize the non-covalent association of hepatitis C virus glycoproteins E1 and E2." Patel J., Patel A.H., McLauchlan J. J. Gen. Virol. 80:1681-1690(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	"Hepatitis C virus core protein interacts with a human DEAD box protein DDX3." Owsianka A.M., Patel A.H. Virology 257:330-340(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION OF CORE PROTEIN WITH HUMAN DDX3X.
[3]	"Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets." McLauchlan J., Lemberg M.K., Hope G., Martoglio B. EMBO J. 21:3980-3988(2002) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE OF CORE PROTEIN BY THE SIGNAL PEPTIDASE, SUBCELLULAR LOCATION, MUTAGENESIS OF 180-ALA--CYS-184.
[4]	"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.
[5]	"Structural biology of hepatitis C virus." Penin F., Dubuisson J., Rey F.A., Moradpour D., Pawlotsky J.-M. Hepatology 39:5-19(2004) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW, SUBCELLULAR LOCATION.
+	Additional computationally mapped references.

Web resources

euHCVdb

The European HCV database

Virus Pathogen Resource

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AY885238 Genomic RNA. Translation: AAW78019.1.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4GAG	X-ray	1.80	P	413-423	[»]

ProteinModelPortal

Q5EG65.

SMR

Q5EG65. Positions 2-45.

ModBase

Search...

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Organism-specific databases

euHCVdb

AY885238.

Family and domain databases

InterPro

IPR002521. HCV_core_C.
IPR002522. HCV_core_N.
IPR002519. HCV_env.
IPR002531. HCV_NS1.
[Graphical view]

Pfam

PF01543. HCV_capsid. 1 hit.
PF01542. HCV_core. 1 hit.
PF01539. HCV_env. 1 hit.
PF01560. HCV_NS1. 1 hit.
[Graphical view]

ProDom

PD001388. HCV_env. 1 hit.
[Graphical view] [Entries sharing at least one domain]

ProtoNet

Search...

Entry information

Entry name

POLG_HCVGL

Accession

Primary (citable) accession number: Q5EG65

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2005
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 69 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program