Reviewed, UniProtKB/Swiss-Prot P26664 (POLG_HCV1)

Names and origin

Protein names	Recommended name:     Genome polyprotein Cleaved into 11 chains:   Recommended name:       Core protein p21   Alternative name(s):       Capsid protein C       p21   Recommended name:       Core protein p19   Recommended name:       Envelope glycoprotein E1   Alternative name(s):       gp32       gp35   Recommended name:       Envelope glycoprotein E2   Alternative name(s):       NS1       gp68       gp70   Recommended name:       p7   Recommended name:       Protease NS2-3         Short name(s)=p23       EC=3.4.22.-   Recommended name:       Serine protease/NTPase/helicase NS3       EC=3.4.21.98       EC=3.6.1.15       EC=3.6.1.-   Alternative name(s):       Hepacivirin       NS3P       p70   Recommended name:       Non-structural protein 4A         Short name(s)=NS4A   Alternative name(s):       p8   Recommended name:       Non-structural protein 4B         Short name(s)=NS4B   Alternative name(s):       p27   Recommended name:       Non-structural protein 5A         Short name(s)=NS5A   Alternative name(s):       p56   Recommended name:       RNA-directed RNA polymerase       EC=2.7.7.48   Alternative name(s):       NS5B       p68
Organism	Hepatitis C virus genotype 1a (isolate 1) (HCV) [Complete proteome]
Taxonomic identifier	11104 [NCBI]
Taxonomic lineage	Viruses › ssRNA positive-strand viruses, no DNA stage › Flaviviridae › Hepacivirus
Virus host	Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	3011 AA.
Sequence status	Complete.
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. 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. 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 a RNA-dependent RNA polymerase that plays an essential role in the virus replication By similarity.
Catalytic activity	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 + H(2)O = NDP + phosphate.
Cofactor	Binds 1 zinc ion per NS3 protease domain By similarity. Binds 1 zinc ion per NS5A N-terminal domain By similarity.
Enzyme regulation	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.
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, 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 By similarity.
Subcellular location	Core protein p21: Endoplasmic reticulum membrane; Single-pass membrane protein. Mitochondrion membrane; Single-pass type I membrane protein. Lipid droplet membrane; Single-pass membrane protein. 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. Core protein p19: Virion. Cytoplasm. Nucleus. Secreted. Envelope glycoprotein E1: Endoplasmic reticulum membrane; Single-pass type I membrane proteinBy 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. Envelope glycoprotein E2: Endoplasmic reticulum membrane; Single-pass type I membrane proteinBy 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. p7: Endoplasmic reticulum membrane; Multi-pass membrane proteinBy similarity. Cell membraneBy 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. Protease NS2-3: Endoplasmic reticulum membrane; Multi-pass membrane proteinPotential. Serine protease/NTPase/helicase NS3: Endoplasmic reticulum membrane; Peripheral membrane proteinBy similarity. Note= NS3 is associated to the ER membrane through its binding to NS4A. Non-structural protein 4A: Endoplasmic reticulum membrane; Single-pass type I membrane proteinPotential. Note= Membrane insertion occurs after processing by the NS3 protease. Non-structural protein 4B: Endoplasmic reticulum membrane; Multi-pass membrane proteinBy similarity. Non-structural protein 5A: Endoplasmic reticulum membrane; Peripheral membrane proteinBy similarity. Cytoplasm › perinuclear regionBy similarity. MitochondrionBy similarity. Note= Membrane insertion occurs after processing by the NS3 protease. RNA-directed RNA polymerase: Endoplasmic reticulum membrane; Single-pass type I membrane proteinPotential. Note= Membrane insertion occurs after processing by the NS3 protease.
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). E2 also contain two segments involved in CD81-binding. HVR1 is implicated in the SCARB1-mediated cell entry. HVR2 and 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. The C-terminus of NS5A contains a variable region called variable region 3 (V3) By similarity. The SH3-binding domain of NS5A is involved in the interaction with human Bin1, GRB2 and Src-family kinases. 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.
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, 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 an 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.
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.
Sequence similarities	Belongs to the hepaciviruses polyprotein family. Contains 1 helicase ATP-binding domain. Contains 1 peptidase C18 domain. Contains 1 peptidase S29 domain. Contains 1 RdRp catalytic domain.
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 Fusion protein Host-virus interaction Interferon antiviral system evasion RNA replication Transcription Transcription regulation
Cellular component	Capsid protein Cell membrane Cytoplasm Endoplasmic reticulum Envelope protein Lipid droplet Membrane Mitochondrion Nucleus Secreted Virion
Coding sequence diversity	Ribosomal frameshifting
Domain	SH3-binding Transmembrane
Ligand	ATP-binding Metal-binding Nucleotide-binding RNA-binding Viral nucleoprotein Zinc
Molecular function	Helicase Hydrolase Nucleotidyltransferase Oncogene Protease RNA-directed RNA polymerase Ribonucleoprotein Serine protease Thiol protease Transferase
PTM	Acetylation Glycoprotein Lipoprotein Palmitate Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Multifunctional enzyme
Gene Ontology (GO)
Cellular component	mitochondrial membrane Inferred from electronic annotation. Source: UniProtKB-SubCell monolayer-surrounded lipid storage body outer lipid monolayer Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	nucleoside-triphosphatase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by ribosomal frameshifting. [Align] [Select]

Notes: The exact location of the ribosomal frameshift is unknown. The F protein seems to be generated by a -2 ribosomal frameshift located in the vicinity of codon 11 of the core protein coding sequence. However, some F proteins may also be generated by +1 ribosomal frameshift. Since the core gene encodes alternative reading frame proteins (ARFPs), many functions depicted for the core protein might belong to the ARFPs.

Isoform Genome polyprotein (identifier: P26664-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Notes: Produced by conventional translation.

Isoform F protein (identifier: P0C044-1)

Also known as: Frameshifted protein;

The sequence of this isoform can be found in the external entry P0C044-1.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Notes: Produced by ribosomal frameshifting.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Initiator methionine	1	1	Removed; by host
	Chain	2 – 191	190	Core protein p21 Potential
	Chain	2 – 177	176	Core protein p19 By similarity
	Propeptide	178 – 191	14	ER anchor for the core protein, removed in mature form by host signal peptidase By similarity
	Chain	192 – 383	192	Envelope glycoprotein E1 Potential
	Chain	384 – 746	363	Envelope glycoprotein E2 Potential
	Chain	747 – 809	63	p7 By similarity
	Chain	810 – 1026	217	Protease NS2-3 Potential
	Chain	1027 – 1657	631	Serine protease/NTPase/helicase NS3 Potential
	Chain	1658 – 1711	54	Non-structural protein 4A Potential
	Chain	1712 – 1972	261	Non-structural protein 4B Potential
	Chain	1973 – 2420	448	Non-structural protein 5A Potential
	Chain	2421 – 3011	591	RNA-directed RNA polymerase Potential
Regions
	Topological domain	2 – 168	167	Cytoplasmic Potential
	Transmembrane	169 – 189	21	Potential
	Topological domain	190 – 358	169	Lumenal Potential
	Transmembrane	359 – 379	21	Potential
	Topological domain	380 – 725	346	Lumenal Potential
	Transmembrane	726 – 746	21	Potential
	Topological domain	747 – 757	11	Lumenal Potential
	Transmembrane	758 – 778	21	Potential
	Topological domain	779 – 782	4	Cytoplasmic Potential
	Transmembrane	783 – 803	21	Potential
	Topological domain	804 – 813	10	Lumenal Potential
	Transmembrane	814 – 834	21	Potential
	Topological domain	835 – 881	47	Cytoplasmic Potential
	Transmembrane	882 – 902	21	Potential
	Topological domain	903 – 928	26	Lumenal Potential
	Transmembrane	929 – 949	21	Potential
	Topological domain	950 – 1657	708	Cytoplasmic Potential
	Transmembrane	1658 – 1678	21	Potential
	Topological domain	1679 – 1805	127	Cytoplasmic Potential
	Transmembrane	1806 – 1826	21	Potential
	Topological domain	1827 – 1828	2	Lumenal Potential
	Transmembrane	1829 – 1849	21	Potential
	Topological domain	1850	1	Cytoplasmic Potential
	Transmembrane	1851 – 1871	21	Potential
	Topological domain	1872 – 1881	10	Lumenal Potential
	Transmembrane	1882 – 1902	21	Potential
	Topological domain	1903 – 1972	70	Cytoplasmic Potential
	Topological domain	1973 – 2002	30	In membrane
	Topological domain	2003 – 2990	988	Cytoplasmic Potential
	Transmembrane	2991 – 3011	21	By similarity
	Domain	1217 – 1369	153	Helicase ATP-binding
	Domain	2634 – 2752	119	RdRp catalytic
	Nucleotide binding	1230 – 1237	8	ATP 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 Probable
	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)