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Entry version 229 (02 Jun 2021)
Sequence version 3 (23 Jan 2007)
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Protein

Genome polyprotein

Gene
N/A
Organism
Hepatitis C virus genotype 1a (isolate H77) (HCV)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the 'correct annotation' for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the 'protein existence' evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

Packages viral RNA to form a viral nucleocapsid, and promotes virion budding (Probable). Participates in the viral particle production as a result of its interaction with the non-structural protein 5A (By similarity).

Binds RNA and may function as a RNA chaperone to induce the RNA structural rearrangements taking place during virus replication (PubMed:18033802).

Modulates viral translation initiation by interacting with viral IRES and 40S ribosomal subunit (By similarity).

Affects various cell signaling pathways, host immunity and lipid metabolism (Probable). Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by blocking the formation of phosphorylated STAT1 and promoting ubiquitin-mediated proteasome-dependent degradation of STAT1 (PubMed:23799612) (By similarity).

Activates STAT3 leading to cellular transformation (By similarity).

Regulates the activity of cellular genes, including c-myc and c-fos (By similarity).

May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm (By similarity).

Represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation (By similarity).

Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NF-kappa-B activation, and activates AP-1 (By similarity).

Binds to dendritic cells (DCs) via C1QR1, resulting in down-regulation of T-lymphocytes proliferation (PubMed:11086025, PubMed:17881511).

Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage (PubMed:14602201).

Induces up-regulation of FAS promoter activity, and thereby contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (PubMed:14602201).

By similarityCurated5 Publications

Forms a heterodimer with envelope glycoprotein E2, which mediates virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane (PubMed:14990718, PubMed:16894197).

Fusion with the host cell is most likely mediated by both E1 and E2, through conformational rearrangements of the heterodimer required for fusion rather than a classical class II fusion mechanism (PubMed:16533059, PubMed:29505618, PubMed:24698129).

E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP) (PubMed:25122793, PubMed:29695434, PubMed:24838241).

APOE associated to the LVP allows the initial virus attachment to cell surface receptors such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SCARB1) (PubMed:12970454, PubMed:12356718, PubMed:12913001, PubMed:28404852, PubMed:22767607).

The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81 (PubMed:22767607, PubMed:12913001).

E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway (PubMed:22855500).

Diffusion of the complex E1/E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry (PubMed:12970454, PubMed:24038151, PubMed:12913001, PubMed:20375010, PubMed:19182773) (By similarity).

By similarity17 Publications

Forms a heterodimer with envelope glycoprotein E1, which mediates virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane (PubMed:14990718, PubMed:16894197).

Fusion with the host cell is most likely mediated by both E1 and E2, through conformational rearrangements of the heterodimer required for fusion rather than a classical class II fusion mechanism (PubMed:16533059, PubMed:29505618, PubMed:24698129).

The interaction between E2 and host apolipoprotein E/APOE allows the proper assembly, maturation and infectivity of the viral particles (PubMed:25122793, PubMed:29695434).

This interaction is probably promoted via the up-regulation of cellular autophagy by the virus (PubMed:29695434).

E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP) (PubMed:25122793, PubMed:29695434, PubMed:24838241).

APOE associated to the LVP allows the initial virus attachment to cell surface receptors such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SCARB1) (PubMed:12970454, PubMed:12356718, PubMed:12913001, PubMed:28404852, PubMed:22767607).

The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81 (PubMed:22767607, PubMed:12913001).

E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway (PubMed:20375010, PubMed:12970454, PubMed:24038151, PubMed:12913001, PubMed:19182773, PubMed:22855500) (By similarity).

Diffusion of the complex E1/E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry (PubMed:20375010, PubMed:12970454, PubMed:24038151, PubMed:12913001, PubMed:19182773) (By similarity).

Inhibits host EIF2AK2/PKR activation, preventing the establishment of an antiviral state (By similarity).

Viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on DCs, and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses (PubMed:15371595).

These interactions allow the capture of circulating HCV particles by these cells and subsequent facilitated transmission to permissive cells such as hepatocytes and lymphocyte subpopulations (PubMed:15371595).

The interaction between E2 and host amino acid transporter complex formed by SLC3A2 and SLC7A5/LAT1 may facilitate viral entry into host cell (PubMed:30341327).

By similarity19 Publications

Ion channel protein that acts as a viroporin and plays an essential role in the assembly, envelopment and secretion of viral particles (PubMed:12719519, PubMed:20824094, PubMed:27320856).

Participates in virus envelopment by coordinating the encounter between NS5A and NS2-based assembly sites loaded with E1/E2 heterodimer, which subsequently leads to nucleocapsid envelopment (By similarity).

Creates a pore in acidic organelles and releases Ca2+ and H+ in the cytoplasm of infected cells, leading to a productive viral infection (Probable) (PubMed:20824094).

High levels of cytoplasmic Ca2+ may trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication (Probable). The release of Ca2+ may also activate the inflamasome leading to chronic inflammation (Probable) (PubMed:31801866).

Targets also host mitochondria and induces mitochondrial depolarization (PubMed:29039530).

In addition of its role as a viroporin, acts as a lipid raft adhesion factor (PubMed:27320856).

1 PublicationBy similarityCurated4 Publications

Cysteine protease required for the proteolytic auto-cleavage between the non-structural proteins NS2 and NS3 (PubMed:8248148).

The N-terminus of NS3 is required for the function of NS2 protease (active region NS2-3) (By similarity).

Promotes the initiation of viral particle assembly by mediating the interaction between structural and non-structural proteins (PubMed:21147927).

By similarity2 Publications

Displays three enzymatic activities: serine protease with a chymotrypsin-like fold, NTPase and RNA helicase (PubMed:25551442).

NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B (PubMed:8189513, PubMed:8035505, PubMed:8386278).

The NS3/NS4A complex prevents phosphorylation of host IRF3, thus preventing the establishment of dsRNA induced antiviral state (By similarity).

The NS3/NS4A complex induces host amino acid transporter component SLC3A2, thus contributing to HCV propagation (PubMed:30341327).

NS3 RNA helicase binds to RNA and unwinds both dsDNA and dsRNA in the 3' to 5' direction, and likely resolves RNA complicated stable secondary structures in the template strand (Probable). Binds a single ATP and catalyzes the unzipping of a single base pair of dsRNA (PubMed:21940894).

Inhibits host antiviral proteins TBK1 and IRF3 thereby preventing the establishment of an antiviral state (By similarity).

Cleaves host MAVS/CARDIF thereby preventing the establishment of an antiviral state (PubMed:16301520, PubMed:16177806).

Cleaves host TICAM1/TRIF, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state (PubMed:15710891).

By similarity1 Publication9 Publications

Peptide cofactor which forms a non-covalent complex with the N-terminal of NS3 serine protease (PubMed:8189513, PubMed:21507982).

The NS3/NS4A complex prevents phosphorylation of host IRF3, thus preventing the establishment of dsRNA induced antiviral state (By similarity).

The NS3/NS4A complex induces host amino acid transporter component SLC3A2, thus contributing to HCV propagation (PubMed:30341327).

By similarity3 Publications

Induces a specific membrane alteration that serves as a scaffold for the virus replication complex (PubMed:12021330).

This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (PubMed:12021330).

NS4B self-interaction contributes to its function in membranous web formation (PubMed:16731940).

Promotes host TRIF protein degradation in a CASP8-dependent manner thereby inhibiting host TLR3-mediated interferon signaling (PubMed:29782532).

Disrupts the interaction between STING and TBK1 contributing to the inhibition of interferon signaling (PubMed:23542348).

4 Publications

Phosphorylated protein that is indispensable for viral replication and assembly (By similarity).

Both hypo- and hyperphosphorylated states are required for the viral life cycle (By similarity).

The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity).

Involved in RNA-binding and especially in binding to the viral genome (Probable). Zinc is essential for RNA-binding (PubMed:20926572).

Participates in the viral particle production as a result of its interaction with the viral mature core protein (By similarity).

Its interaction with host VAPB may target the viral replication complex to vesicles (By similarity).

Down-regulates viral IRES translation initiation (By similarity).

Mediates interferon resistance, presumably by interacting with and inhibiting host EIF2AK2/PKR (PubMed:16951545).

Prevents BIN1-induced apoptosis (PubMed:16530520).

Acts as a transcriptional activator of some host genes important for viral replication when localized in the nucleus (By similarity).

Via the interaction with host PACSIN2, modulates lipid droplet formation in order to promote virion assembly (PubMed:31801866).

Modulates TNFRSF21/DR6 signaling pathway for viral propagation (PubMed:28743875).

By similarity1 Publication5 Publications

RNA-dependent RNA polymerase that performs primer-template recognition and RNA synthesis during viral replication.

1 Publication

Miscellaneous

Viral particle assembly takes place at the surface of ER-derived membranes in close proximity to lipid droplets. NS2 associates with E1/E2 glycoproteins, NS3 and NS5A, which interacts with the viral RNA and core protein to promote genome encapsidation. The nucleocapsid buds at the ER membrane where E1/E2 glycoproteins are anchored and afterward associate with nascent lipid droplet to acquire APOE and APOC. Secretion of viral particles is probably regulated by viroporin p7.Curated
Cell culture adaptation of the virus leads to mutations in NS5A, reducing its inhibitory effect on replication.Curated
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

<p>This subsection of the <a href="http://www.uniprot.org/help/function%5Fsection">Function</a> section describes the catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes.<p><a href='/help/catalytic_activity' target='_top'>More...</a></p>Catalytic activityi

<p>This subsection of the 'Function' section provides information relevant to cofactors. A cofactor is any non-protein substance required for a protein to be catalytically active. Some cofactors are inorganic, such as the metal atoms zinc, iron, and copper in various oxidation states. Others, such as most vitamins, are organic.<p><a href='/help/cofactor' target='_top'>More...</a></p>Cofactori

Protease NS2:
Zn2+By similarityNote: Activity of protease NS2 is dependent on zinc ions and completely inhibited by EDTA. This is probably due to the fact that NS2 protease activity needs NS3 N-terminus that binds a zinc atom (active region NS2-3).By similarity
RNA-directed RNA polymerase:
Mg2+By similarityNote: Binds 2 magnesium ion that constitute a dinuclear catalytic metal center.By similarity
Serine protease/helicase NS3:
Zn2+By similarity, Mg2+By similarityNote: Binds 1 zinc ion, which has a structural role (By similarity). The magnesium ion is essential for the helicase activity (By similarity).By similarity

<p>This subsection of the <a href="http://www.uniprot.org/help/function%5Fsection">Function</a> section describes regulatory mechanisms for enzymes, transporters or microbial transcription factors, and reports the components which regulate (by activation or inhibition) the reaction.<p><a href='/help/activity_regulation' target='_top'>More...</a></p>Activity regulationi

Inhibited by the antiviral drug hexamethylene amiloride (By similarity). Inhibited by amantadine (PubMed:12560074). Inhibition by amantadine appears to be genotype-dependent (By similarity). Also inhibited by long-alkyl-chain iminosugar derivatives (PubMed:12719519).By similarity2 Publications
Activity is up-regulated by PRK2/PKN2-mediated phosphorylation.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/function%5Fsection">Function</a> section is used for enzymes and indicates the residues directly involved in catalysis.<p><a href='/help/act_site' target='_top'>More...</a></p>Active sitei952For protease NS2 activity; shared with dimeric partnerPROSITE-ProRule annotation2 Publications1
Active sitei972For protease NS2 activity; shared with dimeric partnerPROSITE-ProRule annotation1
Active sitei993For protease NS2 activity; shared with dimeric partnerPROSITE-ProRule annotation2 Publications1
Active sitei1083Charge relay system; for serine protease NS3 activityPROSITE-ProRule annotation1 Publication1 Publication1
Active sitei1107Charge relay system; for serine protease NS3 activityPROSITE-ProRule annotation1 Publication1
<p>This subsection of the <a href="http://www.uniprot.org/help/function%5Fsection">Function</a> section indicates at which position the protein binds a given metal ion. The nature of the metal is indicated in the 'Description' field.<p><a href='/help/metal' target='_top'>More...</a></p>Metal bindingi1123Zinc; structural; required for NS3 protease activity and NS2/3 auto-cleavage activityPROSITE-ProRule annotationCombined sources1 Publication1
Metal bindingi1125Zinc; structural; required for NS3 protease activity and NS2/3 auto-cleavage activityPROSITE-ProRule annotationCombined sources1 Publication1
Active sitei1165Charge relay system; for serine protease NS3 activityPROSITE-ProRule annotation1 Publication2 Publications1
Metal bindingi1171Zinc; structural; required for NS3 protease activity and NS2/3 auto-cleavage activityPROSITE-ProRule annotationCombined sources1 Publication1
Metal bindingi1175Zinc; structural; required for NS3 protease activityPROSITE-ProRule annotation1 Publication1
Metal bindingi1237Magnesium; catalytic; for NS3 helicase activityBy similarity1
Metal bindingi1317Magnesium; catalytic; for NS3 helicase activityBy similarity1
Metal bindingi2011Zinc; structuralBy similarity1
Metal bindingi2029Zinc; structuralBy similarity1
Metal bindingi2031Zinc; structuralBy similarity1
Metal bindingi2052Zinc; structuralBy similarity1
Metal bindingi2640Magnesium; catalytic; for RNA-directed RNA polymerase activityBy similarity1
Metal bindingi2738Magnesium; catalytic; for RNA-directed RNA polymerase activityBy similarity1
Metal bindingi2739Magnesium; catalytic; for RNA-directed RNA polymerase activityBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/function%5Fsection">Function</a> section describes a region in the protein which binds nucleotide phosphates. It always involves more than one amino acid and includes all residues involved in nucleotide-binding.<p><a href='/help/np_bind' target='_top'>More...</a></p>Nucleotide bindingi1230 – 1237ATPPROSITE-ProRule annotation8

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionHelicase, Hydrolase, Ion channel, Multifunctional enzyme, Nucleotidyltransferase, Protease, Ribonucleoprotein, RNA-binding, RNA-directed RNA polymerase, Serine protease, Thiol protease, Transferase, Viral ion channel, Viral nucleoprotein
Biological processActivation 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 adhesion receptor, Viral attachment to host cell, Viral attachment to host entry receptor, Viral immunoevasion, Viral penetration into host cytoplasm, Viral RNA replication, Virus endocytosis by host, Virus entry into host cell
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BRENDA Comprehensive Enzyme Information System

More...
BRENDAi
3.4.21.98, 17003

Reactome - a knowledgebase of biological pathways and processes

More...
Reactomei
R-HSA-8854214, TBC/RABGAPs

Protein family/group databases

MEROPS protease database

More...
MEROPSi
S29.001

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names%5Fand%5Ftaxonomy%5Fsection">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Recommended name:
Genome polyprotein
Cleaved into the following 11 chains:
Alternative name(s):
Capsid protein C
p23
Alternative name(s):
p21
Alternative name(s):
gp32
gp35
Alternative name(s):
NS1
gp68
gp70
Protease NS2 (EC:3.4.22.-By similarity)
Short name:
p23
Alternative name(s):
Non-structural protein 2
Short name:
NS2
Serine protease/helicase NS3 (EC:3.4.21.982 Publications, EC:3.6.1.153 Publications, EC:3.6.4.133 Publications)
Alternative name(s):
Hepacivirin
NS3 helicase1 Publication
NS3 protease1 Publication
NS3P
Viroporin p70
Alternative name(s):
p8
Alternative name(s):
p27
Alternative name(s):
p56/58
RNA-directed RNA polymerase (EC:2.7.7.481 Publication)
Alternative name(s):
NS5B
p68
<p>This subsection of the <a href="http://www.uniprot.org/help/names%5Fand%5Ftaxonomy%5Fsection">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>OrganismiHepatitis C virus genotype 1a (isolate H77) (HCV)
<p>This subsection of the <a href="http://www.uniprot.org/help/names%5Fand%5Ftaxonomy%5Fsection">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the 'taxonomic identifier' or 'taxid'.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri63746 [NCBI]
<p>This subsection of the <a href="http://www.uniprot.org/help/names%5Fand%5Ftaxonomy%5Fsection">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineageiVirusesRiboviriaOrthornaviraeKitrinoviricotaFlasuviricetesAmarilloviralesFlaviviridaeHepacivirus
<p>This subsection of the <a href="http://www.uniprot.org/help/names%5Fand%5Ftaxonomy%5Fsection">Names and taxonomy</a> section only exists in viral entries and indicates the host(s) either as a specific organism or taxonomic group of organisms that are susceptible to be infected by a virus.<p><a href='/help/virus_host' target='_top'>More...</a></p>Virus hostiHomo sapiens (Human) [TaxID: 9606]
<p>This subsection of the <a href="http://www.uniprot.org/help/names%5Fand%5Ftaxonomy%5Fsection">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
  • UP000180556 <p>A UniProt <a href="http://www.uniprot.org/manual/proteomes%5Fmanual">proteome</a> can consist of several components.<br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Genome
  • UP000115192 Componenti: Genome
  • UP000000518 Componenti: Genome

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular%5Flocation%5Fsection">'Subcellular location'</a> section describes the subcellular compartment where each non-membrane region of a membrane-spanning protein is found.<p><a href='/help/topo_dom' target='_top'>More...</a></p>Topological domaini2 – 168CytoplasmicSequence analysisAdd BLAST167
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular%5Flocation%5Fsection">'Subcellular location'</a> section describes the extent of a membrane-spanning region of the protein. It denotes the presence of both alpha-helical transmembrane regions and the membrane spanning regions of beta-barrel transmembrane proteins.<p><a href='/help/transmem' target='_top'>More...</a></p>Transmembranei169 – 189HelicalSequence analysisAdd BLAST21
Topological domaini190 – 358Lumenal1 PublicationAdd BLAST169
Transmembranei359 – 379Helical1 PublicationAdd BLAST21
Topological domaini380 – 725Lumenal1 PublicationAdd BLAST346
Transmembranei726 – 746Helical1 PublicationAdd BLAST21
Topological domaini747 – 757Lumenal2 PublicationsAdd BLAST11
Transmembranei758 – 778Helical2 PublicationsAdd BLAST21
Topological domaini779 – 781Cytoplasmic2 Publications3
Transmembranei782 – 803Helical2 PublicationsAdd BLAST22
Topological domaini804 – 813Lumenal2 Publications10
Transmembranei814 – 834HelicalBy similarityAdd BLAST21
Topological domaini835 – 838CytoplasmicBy similarity4
Transmembranei839 – 859HelicalBy similarityAdd BLAST21
Topological domaini860 – 881LumenalBy similarityAdd BLAST22
Transmembranei882 – 902HelicalBy similarityAdd BLAST21
Topological domaini903 – 1657CytoplasmicBy similarityAdd BLAST755
Transmembranei1658 – 1678HelicalSequence analysisAdd BLAST21
Topological domaini1679 – 1805CytoplasmicSequence analysisAdd BLAST127
Transmembranei1806 – 1824HelicalSequence analysisAdd BLAST19
Topological domaini1825 – 1828Lumenal1 Publication4
Transmembranei1829 – 1849HelicalSequence analysisAdd BLAST21
Topological domaini1850CytoplasmicSequence analysis1
Transmembranei1851 – 1871HelicalSequence analysisAdd BLAST21
Topological domaini1872 – 1881LumenalSequence analysis10
Transmembranei1882 – 1902HelicalSequence analysisAdd BLAST21
Topological domaini1903 – 1972CytoplasmicSequence analysisAdd BLAST70
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular%5Flocation%5Fsection">'Subcellular location'</a> section describes the extent of a region that is buried within a membrane, but does not cross it.<p><a href='/help/intramem' target='_top'>More...</a></p>Intramembranei1973 – 20031 Publication1 PublicationAdd BLAST31
Topological domaini2004 – 2990Cytoplasmic1 PublicationAdd BLAST987
Transmembranei2991 – 3011Helical1 PublicationAdd BLAST21

Keywords - Cellular componenti

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

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology%5Fand%5Fbiotech%5Fsection">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi399L → R: Complete loss of E2 binding to host SCARB1; 5-10-fold decrease of infectivity for the viral particles. 1 Publication1
Mutagenesisi429C → A: Complete loss of infectivity. 1 Publication1
Mutagenesisi452C → A: Complete loss of infectivity. Loss of heterodimerization with E1. No effect on CD81-binding function. 1 Publication1
Mutagenesisi459C → A: Complete loss of infectivity. Loss of heterodimerization with E1. 78% loss of CD81-binding function. 1 Publication1
Mutagenesisi486C → A: Complete loss of infectivity. No effect on CD81-binding function. Loss of heterodimerization with E1. 1 Publication1
Mutagenesisi494C → A: Complete loss of infectivity and CD81-binding function. Loss of heterodimerization with E1. 1 Publication1
Mutagenesisi503C → A: Complete loss of infectivity and CD81-binding function. 1 Publication1
Mutagenesisi508C → A: Complete loss of infectivity and CD81-binding function. 1 Publication1
Mutagenesisi552C → A: Complete loss of infectivity. 1 Publication1
Mutagenesisi564C → A: Complete loss of infectivity and CD81-binding function. 1 Publication1
Mutagenesisi569C → A: Complete loss of infectivity. No effect on CD81-binding function. Loss of heterodimerization with E1. 1 Publication1
Mutagenesisi581C → A: Complete loss of infectivity. No effect on CD81-binding function. Loss of heterodimerization with E1. 1 Publication1
Mutagenesisi585C → A: Complete loss of infectivity. No effect on CD81-binding function. Loss of heterodimerization with E1. 1 Publication1
Mutagenesisi597C → A: Complete loss of infectivity. Reduced CD81-binding function. 1 Publication1
Mutagenesisi607C → A: Complete loss of infectivity. Complete loss of E2 expression probably due to the disruption of the global conformation of the protein. 1 Publication1
Mutagenesisi620C → A: Complete loss of infectivity. Reduced CD81-binding function. 1 Publication1
Mutagenesisi644C → A: Complete loss of infectivity. Complete loss of E2 expression probably due to the disruption of the global conformation of the protein. 1 Publication1
Mutagenesisi652C → A: Complete loss of infectivity. Reduced heterodimerization with E1. No effect on CD81-binding function. 1 Publication1
Mutagenesisi677C → A: Complete loss of infectivity. Reduced heterodimerization with E1. No effect on CD81-binding function. 1 Publication1
Mutagenesisi720V → L: Increases processing between E2 and p7. 1 Publication1
Mutagenesisi779K → I: Virus can no longer infect chimpanzee. 1 Publication1
Mutagenesisi781R → S: Virus can no longer infect chimpanzee. 1 Publication1
Mutagenesisi922C → S: Complete loss of palmitoylation of NS2. 1 Publication1
Mutagenesisi952H → A: Complete loss of NS2-NS3 cleavage. 2 Publications1
Mutagenesisi993C → A: Complete loss of NS2-NS3 cleavage. 2 Publications1
Mutagenesisi1083H → A: Complete loss of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B cleavages. 1 Publication1
Mutagenesisi1165S → A: Complete loss of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B cleavages. 2 Publications1
Mutagenesisi1968C → A: Strong decrease in NS4B palmitoylation. 1 Publication1
Mutagenesisi1972C → A: Slight decrease in NS4B palmitoylation. 1 Publication1
Mutagenesisi2321S → A: Loss of phosphorylation. 1 Publication1

Keywords - Diseasei

Oncogene

Chemistry databases

ChEMBL database of bioactive drug-like small molecules

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ChEMBLi
CHEMBL3638344

Drug and drug target database

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DrugBanki
DB08644, {1-[2-(1-FORMYL-PROPYL)-3-METHANESULFONYLAMINO-PYRROLIDINE-1-CARBONYL]-2-METHYL-PROPYL}-CARBAMIC ACID TERT-BUTYL ESTER

DrugCentral

More...
DrugCentrali
P27958

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm%5Fprocessing%5Fsection">PTM / Processing</a> section indicates that the initiator methionine is cleaved from the mature protein.<p><a href='/help/init_met' target='_top'>More...</a></p>Initiator methionineiRemoved; by hostBy similarity
<p>This subsection of the 'PTM / Processing' section describes the extent of a polypeptide chain in the mature protein following processing or proteolytic cleavage.<p><a href='/help/chain' target='_top'>More...</a></p>ChainiPRO_00004508542 – 3011Genome polyproteinAdd BLAST3010
ChainiPRO_00000375662 – 191Core protein precursorAdd BLAST190
ChainiPRO_00000375672 – 177Mature core proteinAdd BLAST176
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm%5Fprocessing%5Fsection">PTM / Processing</a> section describes a propeptide, which is a part of a protein that is cleaved during maturation or activation. Once cleaved, a propeptide generally has no independent biological function.<p><a href='/help/propep' target='_top'>More...</a></p>PropeptideiPRO_0000037568178 – 191ER anchor for the core protein, removed in mature form by host signal peptidase1 PublicationAdd BLAST14
ChainiPRO_0000037569192 – 383Envelope glycoprotein E1Add BLAST192
ChainiPRO_0000037570384 – 746Envelope glycoprotein E2Add BLAST363
ChainiPRO_0000037571747 – 809Viroporin p7Add BLAST63
ChainiPRO_0000037572810 – 1026Protease NS2PROSITE-ProRule annotationAdd BLAST217
ChainiPRO_00000375731027 – 1657Serine protease/helicase NS3Add BLAST631
ChainiPRO_00000375741658 – 1711Non-structural protein 4AAdd BLAST54
ChainiPRO_00000375751712 – 1972Non-structural protein 4BAdd BLAST261
ChainiPRO_00000375761973 – 2420Non-structural protein 5AAdd BLAST448
ChainiPRO_00000375772421 – 3011RNA-directed RNA polymeraseAdd BLAST591

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the 'PTM / Processing' section specifies the position and type of each modified residue excluding <a href="http://www.uniprot.org/manual/lipid">lipids</a>, <a href="http://www.uniprot.org/manual/carbohyd">glycans</a> and <a href="http://www.uniprot.org/manual/crosslnk">protein cross-links</a>.<p><a href='/help/mod_res' target='_top'>More...</a></p>Modified residuei2N-acetylserine; by hostBy similarity1
Modified residuei53Phosphoserine; by hostBy similarity1
Modified residuei99Phosphoserine; by hostBy similarity1
Modified residuei116Phosphoserine; by host PKABy similarity1
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm%5Fprocessing%5Fsection">PTM / Processing</a> section specifies the position and type of each covalently attached glycan group (mono-, di-, or polysaccharide).<p><a href='/help/carbohyd' target='_top'>More...</a></p>Glycosylationi196N-linked (GlcNAc...) asparagine; by host1 Publication1
Glycosylationi209N-linked (GlcNAc...) asparagine; by host1 Publication1
Glycosylationi234N-linked (GlcNAc...) asparagine; by host1 Publication1
Glycosylationi305N-linked (GlcNAc...) asparagine; by host1 Publication1
Glycosylationi417N-linked (GlcNAc...) (high mannose) asparagine; by host1 Publication1
Glycosylationi423N-linked (GlcNAc...) (high mannose) asparagine; by host1 Publication1
<p>This subsection of the PTM / Processing":/help/ptm_processing_section section describes the positions of cysteine residues participating in disulfide bonds.<p><a href='/help/disulfid' target='_top'>More...</a></p>Disulfide bondi429 ↔ 5521 Publication
Glycosylationi430N-linked (GlcNAc...) (high mannose) asparagine; by host2 Publications1
Glycosylationi448N-linked (GlcNAc...) (high mannose) asparagine; by host1 Publication1
Disulfide bondi452 ↔ 4591 Publication
Glycosylationi476N-linked (GlcNAc...) (high mannose) asparagine; by host1 Publication1
Disulfide bondi486 ↔ 4941 Publication
Disulfide bondi503 ↔ 5081 Publication
Glycosylationi532N-linked (GlcNAc...) (high mannose) asparagine; by host2 Publications1
Glycosylationi540N-linked (GlcNAc...) (high mannose) asparagine; by host1 Publication1
Glycosylationi556N-linked (GlcNAc...) (high mannose) asparagine; by host2 Publications1
Disulfide bondi564 ↔ 5691 Publication
Glycosylationi576N-linked (GlcNAc...) (high mannose) asparagine; by host1 Publication1
Disulfide bondi581 ↔ 5851 Publication
Disulfide bondi597 ↔ 6201 Publication
Disulfide bondi607 ↔ 6441 Publication
Glycosylationi623N-linked (GlcNAc...) (high mannose) asparagine; by host2 Publications1
Glycosylationi645N-linked (GlcNAc...) (high mannose) asparagine; by host1 Publication1
Disulfide bondi652 ↔ 6771 Publication
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm%5Fprocessing%5Fsection">PTM / Processing</a> section specifies the position(s) and the type of covalently attached lipid group(s).<p><a href='/help/lipid' target='_top'>More...</a></p>Lipidationi922S-palmitoyl cysteine; by host1 Publication1
Lipidationi1968S-palmitoyl cysteine; by host1 Publication1
Lipidationi1972S-palmitoyl cysteine; by host; partial1 Publication1
Modified residuei2194Phosphoserine; by host; in p56By similarity1
Modified residuei2197Phosphoserine; by host; in p58By similarity1
Modified residuei2201Phosphoserine; by host; in p56 and p58, regulates intracellular NS5A distributionBy similarity1
Modified residuei2204Phosphoserine; by host; in p58By similarity1
Modified residuei2207Phosphoserine; by host; in p58By similarity1
Modified residuei2210Phosphoserine; by host; in p58By similarity1
Modified residuei2321Phosphoserine; by host1 Publication1
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm%5Fprocessing%5Fsection">PTM / Processing</a> section describes <strong>covalent linkages</strong> of various types formed <strong>between two proteins (interchain cross-links)</strong> or <strong>between two parts of the same protein (intrachain cross-links)</strong>, except the disulfide bonds that are annotated in the <a href="http://www.uniprot.org/manual/disulfid">'Disulfide bond'</a> subsection.<p><a href='/help/crosslnk' target='_top'>More...</a></p>Cross-linki2350Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei2449Phosphoserine; by hostBy similarity1
Modified residuei2462Phosphoserine; by hostBy similarity1

<p>This subsection of the <a href="http://www.uniprot.org/help/ptm%5Fprocessing%5Fsection">PTM/processing</a> section describes post-translational modifications (PTMs). This subsection <strong>complements</strong> the information provided at the sequence level or describes modifications for which <strong>position-specific data is not yet available</strong>.<p><a href='/help/post-translational_modification' target='_top'>More...</a></p>Post-translational modificationi

Specific enzymatic cleavages in vivo yield mature proteins (PubMed:8189513, PubMed:15722527, PubMed:8035505, PubMed:8386278). The structural proteins, core, E1, E2 and p7 are produced by proteolytic processing by host signal peptidases (PubMed:15247249). The core protein precursor is synthesized as a 23 kDa, which is retained in the ER membrane through the hydrophobic signal peptide (By similarity). Cleavage by the signal peptidase releases the 21 kDa mature core protein (By similarity). The cleavage of the core protein precursor occurs between aminoacids 176 and 188 but the exact cleavage site is not known (By similarity). Some degraded forms of the core protein appear as well during the course of infection (By similarity). The other proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) are cleaved by the viral proteases (PubMed:15247249, PubMed:7679746, PubMed:8189513, PubMed:8035505, PubMed:8386278). Autoprocessing between NS2 and NS3 is mediated by the NS2 cysteine protease catalytic domain and regulated by the NS3 N-terminal domain (By similarity).By similarity6 Publications
Phosphorylated by host PKC and PKA.By similarity
Ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation.By similarity
Highly N-glycosylated.1 Publication
Highly N-glycosylated.2 Publications
Palmitoylation is required for NS2/3 autoprocessing and E2 recruitment to membranes.1 Publication
Palmitoylated. This modification may play a role in its polymerization or in protein-protein interactions.1 Publication
Cleaved by host caspases which are probably activated by the viral infection.By similarity
Ubiquitinated (PubMed:27194766). Ubiquitination, most probably at Lys-2350, mediated by host IFI27 and SKP2 leads to proteasomal degradation, restricting viral infection (PubMed:27194766).1 Publication
Phosphorylated on serines in a basal form termed p56 (By similarity). p58 is a hyperphosphorylated form of p56 (By similarity). p56 and p58 coexist in the cell in roughly equivalent amounts (By similarity). Hyperphosphorylation is dependent on the presence of NS4A (By similarity). Host CSNK1A1/CKI-alpha, PI4KA or RPS6KB1 kinases may be responsible for NS5A phosphorylation (By similarity). Phosphorylated NS5A is involved in viral replication (By similarity).By similarity
Tyrosine phosphorylation is essential for the interaction with host SRC.By similarity
The N-terminus is phosphorylated by host PRK2/PKN2.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections ('Function', 'PTM / Processing', 'Pathology and Biotech') according to its content.<p><a href='/help/site' target='_top'>More...</a></p>Sitei177 – 178Cleavage; by host signal peptide peptidaseBy similarity2
Sitei191 – 192Cleavage; by host signal peptidaseBy similarity2
Sitei383 – 384Cleavage; by host signal peptidaseBy similarity2
Sitei746 – 747Cleavage; by host signal peptidase2
Sitei809 – 810Cleavage; by host signal peptidase2
Sitei1026 – 1027Cleavage; by protease NS2PROSITE-ProRule annotation2
Sitei1657 – 1658Cleavage; by serine protease/helicase NS31 Publication2
Sitei1711 – 1712Cleavage; by serine protease/helicase NS31 Publication2
Sitei1972 – 1973Cleavage; by serine protease/helicase NS31 Publication2
Sitei2420 – 2421Cleavage; by serine protease/helicase NS31 Publication2

Keywords - PTMi

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

Proteomic databases

PRoteomics IDEntifications database

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PRIDEi
P27958

PTM databases

GlyGen: Computational and Informatics Resources for Glycoscience

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GlyGeni
P27958, 15 sites, 14 N-linked glycans (11 sites)

iPTMnet integrated resource for PTMs in systems biology context

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iPTMneti
P27958

SwissPalm database of S-palmitoylation events

More...
SwissPalmi
P27958

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

<p>This subsection of the 'Expression' section reports the experimentally proven effects of inducers and repressors (usually chemical compounds or environmental factors) on the level of protein (or mRNA) expression (up-regulation, down-regulation, constitutive expression).<p><a href='/help/induction' target='_top'>More...</a></p>Inductioni

Expressed late in the infection cycle.1 Publication

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

<p>This subsection of the <a href="http://www.uniprot.org/help/interaction%5Fsection">'Interaction'</a> section provides information about the protein quaternary structure and interaction(s) with other proteins or protein complexes (with the exception of physiological receptor-ligand interactions which are annotated in the <a href="http://www.uniprot.org/help/function%5Fsection">'Function'</a> section).<p><a href='/help/subunit_structure' target='_top'>More...</a></p>Subunit structurei

Homooligomer (PubMed:25351725).

Interacts with E1 (via C-terminus) (PubMed:8764026).

Interacts with the non-structural protein 5A (By similarity).

Interacts (via N-terminus) with host STAT1 (via SH2 domain); this interaction results in decreased STAT1 phosphorylation and ubiquitin-mediated proteasome-dependent STAT1 degradation, leading to decreased IFN-stimulated gene transcription (PubMed:23799612).

Interacts with host STAT3; this interaction constitutively activates STAT3 (By similarity). Associates with host LTBR receptor (By similarity).

Interacts with host TNFRSF1A receptor and possibly induces apoptosis (By similarity).

Interacts with host HNRPK (By similarity).

Interacts with host YWHAE (By similarity).

Interacts with host UBE3A/E6AP (By similarity).

Interacts with host DDX3X (By similarity).

Interacts with host APOA2 (By similarity).

Interacts with host RXRA protein (By similarity).

Interacts with host SP110 isoform 3/Sp110b; this interaction sequesters the transcriptional corepressor SP110 away from the nucleus (By similarity).

Interacts with host CREB3 nuclear transcription protein; this interaction triggers cell transformation (By similarity).

Interacts with host ACY3 (PubMed:19486448).

Interacts with host C1QR1 (PubMed:11086025).

Interacts with host RBM24; this interaction, which enhances the interaction of the mature core protein with 5'-UTR, may inhibit viral translation and favor replication (By similarity).

Interacts (via N-terminus) with host EIF2AK2/PKR (via N-terminus); this interaction induces the autophosphorylation of EIF2AK2 (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).

By similarity5 Publications

Forms a heterodimer with envelope glycoprotein E2 (PubMed:11145889, PubMed:14990718, PubMed:24038151).

Interacts with mature core protein (PubMed:8764026).

Interacts with protease NS2 (PubMed:21147927). The heterodimer E1/E2 interacts with host CLDN1; this interaction plays a role in viral entry into host cell (PubMed:24038151).

Interacts with host SPSB2 (via C-terminus) (PubMed:31344133). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).

By similarity6 Publications

Forms a heterodimer with envelope glycoprotein E1 (PubMed:11145889, PubMed:14990718, PubMed:24038151).

Interacts with host CD81 and SCARB1 receptors; these interactions play a role in viral entry into host cell (PubMed:12970454, PubMed:12356718, PubMed:12913001).

Interacts with host EIF2AK2/PKR; this interaction inhibits EIF2AK2 and probably allows the virus to evade the innate immune response (PubMed:10390359).

Interacts with host CD209/DC-SIGN and CLEC4M/DC-SIGNR (PubMed:15371595). Interact with host SPCS1; this interaction is essential for viral particle assembly (By similarity).

Interacts with protease NS2 (PubMed:21147927). The heterodimer E1/E2 interacts with host CLDN1; this interaction plays a role in viral entry into host cell (PubMed:24038151). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).

Interacts with host SLC3A2/4F2hc; the interaction may facilitate viral entry into host cell (PubMed:30341327).

Interacts with human PLSCR1 (By similarity).

By similarity10 Publications

Homohexamer (PubMed:12560074). Homoheptamer (By similarity).

Interacts with protease NS2 (By similarity).

By similarity1 Publication

Homodimer (PubMed:16862121).

Interacts with host SPCS1; this interaction is essential for viral particle assembly (By similarity).

Interacts with envelope glycoprotein E1 (PubMed:21147927).

Interacts with envelope glycoprotein E2 (PubMed:21147927).

Interacts with viroporin p7 (By similarity).

Interacts with serine protease/helicase NS3 (PubMed:21147927). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12692249, PubMed:12692242). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).

By similarity4 Publications

Interacts with protease NS2 (PubMed:21147927).

Interacts with non-structural protein 4A; this interaction stabilizes the folding of NS3 serine protease (By similarity). NS3-NS4A interaction is essential for NS3 activation and allows membrane anchorage of the latter (PubMed:7769699, PubMed:8861917). NS3/NS4A complex also prevents phosphorylation of host IRF3, thus preventing the establishment of dsRNA induced antiviral state (By similarity).

Interacts with host MAVS; this interaction leads to the cleavage and inhibition of host MAVS (PubMed:16177806, PubMed:16301520).

Interacts with host TICAM1; this interaction leads to the cleavage and inhibition of host TICAM1 (PubMed:16177806, PubMed:16301520).

Interacts with host TANK-binding kinase/TBK1; this interaction results in the inhibition of the association between TBK1 and IRF3, which leads to the inhibition of IRF3 activation (By similarity).

Interacts with host RBM24 (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692249, PubMed:12692242). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).

By similarity8 Publications

Interacts with NS3 serine protease; this interaction stabilizes the folding of NS3 serine protease (PubMed:8861917, PubMed:7769699). NS3-NS4A interaction is essential for NS3 activation and allows membrane anchorage of the latter (PubMed:8861917, PubMed:7769699).

Interacts with non-structural protein 5A (via N-terminus) (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692249, PubMed:12692242). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity).

By similarity5 Publications

Homomultimer (PubMed:23868571).

Interacts with non-structural protein NS5A (PubMed:23868571).

Interacts with host PLA2G4C; this interaction likely initiates the recruitment of replication complexes to lipid droplets (By similarity).

Interacts with host STING; this interaction disrupts the interaction between STING and TBK1 thereby suppressing the interferon signaling (PubMed:23542348). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692249, PubMed:12692242).

By similarity5 Publications

Monomer (PubMed:20926572). Homodimer; dimerization is required for RNA-binding (PubMed:20926572).

Interacts with the mature core protein (By similarity).

Interacts (via N-terminus) with non-structural protein 4A (By similarity).

Interacts with non-structural protein 4B (PubMed:23868571).

Interacts (via region D2) with RNA-directed RNA polymerase (Probable). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692249, PubMed:12692242).

Interacts with host GRB2 (By similarity).

Interacts with host BIN1 (PubMed:16530520).

Interacts with host PIK3R1 (By similarity).

Interacts with host SRCAP (PubMed:10702287).

Interacts with host FKBP8 (By similarity).

Interacts (via C-terminus) with host VAPB (via MSP domain) (PubMed:22720086) (Probable).

Interacts with host EIF2AK2/PKR; this interaction leads to disruption of EIF2AK2 dimerization by NS5A and probably allows the virus to evade the innate immune response (Probable).

Interacts (via N-terminus) with host PACSIN2 (via N-terminus); this interaction attenuates protein kinase C alpha-mediated phosphorylation of PACSIN2 by disrupting the interaction between PACSIN2 and PRKCA (PubMed:31801866).

Interacts (via N-terminus) with host SRC kinase (via SH2 domain) (By similarity).

Interacts with most Src-family kinases (By similarity).

Interacts with host IFI27 and SKP2; promotes the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766).

Interacts with host GPS2 (By similarity).

Interacts with host TNFRSF21; this interaction allows the modulation by the virus of JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent manner (PubMed:28743875).

Interacts (via N-terminus) with host CIDEB (via N-terminus); this interaction seems to regulate the association of HCV particles with APOE (PubMed:27282740).

Interacts with host CHKA/Choline Kinase-alpha; CHKA bridges host PI4KA and NS5A and potentiates NS5A-stimulated PI4KA activity, which then facilitates the targeting of the ternary complex to the ER for viral replication (By similarity).

Interacts with host SPSB2 (via C-terminus); this interaction targets NS5A for ubiquitination and degradation (PubMed:31344133).

Interacts with host RAB18; this interaction may promote the association of NS5A and other replicase components with lipid droplets (By similarity).

Interacts (via region D2) with host PPIA/CYPA; the interaction stimulates RNA-binding ability of NS5A and is dependent on the peptidyl-prolyl cis-trans isomerase activity of PPIA/CYPA (Probable).

By similarity4 Publications14 Publications

Homooligomer.

Interacts with non-structural protein 5A (PubMed:11801599).

Interacts with host VAPB (By similarity).

Interacts with host PRK2/PKN2 (PubMed:15364941).

Interacts with host HNRNPA1 and SEPT6; these interactions facilitate the viral replication (PubMed:17229681). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (PubMed:12021330, PubMed:12692249, PubMed:12692242).

By similarity6 Publications

<p>This subsection of the '<a href="http://www.uniprot.org/help/interaction%5Fsection">Interaction&l