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Genome polyprotein [Cleaved into: Core protein precursor (Capsid protein C) (p23); Mature core protein (p21); Envelope glycoprotein E1 (gp32) (gp35); Envelope glycoprotein E2 (NS1) (gp68) (gp70); Viroporin p7; Protease NS2 (p23) (EC 3.4.22.-) (Non-structural protein 2) (NS2); Serine protease/helicase NS3 (EC 3.4.21.98) (EC 3.6.1.15) (EC 3.6.4.13) (Hepacivirin) (NS3 helicase) (NS3 protease) (NS3P) (Viroporin p70); Non-structural protein 4A (NS4A) (p8); Non-structural protein 4B (NS4B) (p27); Non-structural protein 5A (NS5A) (p56/58); RNA-directed RNA polymerase (EC 2.7.7.48) (NS5B) (p68)]

 POLG_HCVJ6              Reviewed;        3033 AA.
P26660;
01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
23-JAN-2007, sequence version 3.
29-SEP-2021, entry version 190.
RecName: Full=Genome polyprotein;
Contains:
RecName: Full=Core protein precursor;
AltName: Full=Capsid protein C;
AltName: Full=p23;
Contains:
RecName: Full=Mature core protein;
AltName: Full=p21;
Contains:
RecName: Full=Envelope glycoprotein E1;
AltName: Full=gp32;
AltName: Full=gp35;
Contains:
RecName: Full=Envelope glycoprotein E2;
AltName: Full=NS1;
AltName: Full=gp68;
AltName: Full=gp70;
Contains:
RecName: Full=Viroporin p7;
Contains:
RecName: Full=Protease NS2;
Short=p23;
EC=3.4.22.- {ECO:0000250|UniProtKB:P26663};
AltName: Full=Non-structural protein 2;
Short=NS2;
Contains:
RecName: Full=Serine protease/helicase NS3;
EC=3.4.21.98 {ECO:0000250|UniProtKB:P27958};
EC=3.6.1.15 {ECO:0000250|UniProtKB:P27958};
EC=3.6.4.13 {ECO:0000250|UniProtKB:P27958};
AltName: Full=Hepacivirin;
AltName: Full=NS3 helicase {ECO:0000250|UniProtKB:P27958};
AltName: Full=NS3 protease {ECO:0000250|UniProtKB:P27958};
AltName: Full=NS3P;
AltName: Full=Viroporin p70;
Contains:
RecName: Full=Non-structural protein 4A;
Short=NS4A;
AltName: Full=p8;
Contains:
RecName: Full=Non-structural protein 4B;
Short=NS4B;
AltName: Full=p27;
Contains:
RecName: Full=Non-structural protein 5A;
Short=NS5A;
AltName: Full=p56/58;
Contains:
RecName: Full=RNA-directed RNA polymerase;
EC=2.7.7.48 {ECO:0000269|PubMed:21209117};
AltName: Full=NS5B;
AltName: Full=p68;
Hepatitis C virus genotype 2a (isolate HC-J6) (HCV).
Viruses; Riboviria; Orthornavirae; Kitrinoviricota; Flasuviricetes;
Amarillovirales; Flaviviridae; Hepacivirus.
NCBI_TaxID=11113;
NCBI_TaxID=9606; Homo sapiens (Human).
[1]
NUCLEOTIDE SEQUENCE [GENOMIC RNA].
PubMed=1658196; DOI=10.1099/0022-1317-72-11-2697;
Okamoto H., Okada S., Sugiyama Y., Kurai K., Lizuka H., Machida A.,
Miyakawa Y., Mayumi M.;
"Nucleotide sequence of the genomic RNA of hepatitis C virus isolated from
a human carrier: comparison with reported isolates for conserved and
divergent regions.";
J. Gen. Virol. 72:2697-2704(1991).
[2]
REVIEW.
PubMed=10718937; DOI=10.1046/j.1365-2893.2000.00201.x;
McLauchlan J.;
"Properties of the hepatitis C virus core protein: a structural protein
that modulates cellular processes.";
J. Viral Hepat. 7:2-14(2000).
[3]
REVIEW.
PubMed=14752815; DOI=10.1002/hep.20032;
Penin F., Dubuisson J., Rey F.A., Moradpour D., Pawlotsky J.-M.;
"Structural biology of hepatitis C virus.";
Hepatology 39:5-19(2004).
[4]
X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 2443-3012.
PubMed=15746101; DOI=10.1074/jbc.m413410200;
Biswal B.K., Cherney M.M., Wang M., Chan L., Yannopoulos C.G.,
Bilimoria D., Nicolas O., Bedard J., James M.N.G.;
"Crystal structures of the RNA-dependent RNA polymerase genotype 2a of
hepatitis C virus reveal two conformations and suggest mechanisms of
inhibition by non-nucleoside inhibitors.";
J. Biol. Chem. 280:18202-18210(2005).
[5] {ECO:0007744|PDB:2XWH}
X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 2443-3005, AND CATALYTIC ACTIVITY
(RNA-DIRECTED RNA POLYMERASE).
PubMed=21209117; DOI=10.1128/jvi.02177-10;
Schmitt M., Scrima N., Radujkovic D., Caillet-Saguy C., Simister P.C.,
Friebe P., Wicht O., Klein R., Bartenschlager R., Lohmann V.,
Bressanelli S.;
"A comprehensive structure-function comparison of hepatitis C virus strain
JFH1 and J6 polymerases reveals a key residue stimulating replication in
cell culture across genotypes.";
J. Virol. 85:2565-2581(2011).
[6] {ECO:0007744|PDB:4ADP}
X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 2443-3012, AND MUTAGENESIS OF
VAL-2847.
PubMed=22532694; DOI=10.1128/jvi.00459-12;
Scrima N., Caillet-Saguy C., Ventura M., Harrus D., Astier-Gin T.,
Bressanelli S.;
"Two crucial early steps in RNA synthesis by the hepatitis C virus
polymerase involve a dual role of residue 405.";
J. Virol. 86:7107-7117(2012).
-!- FUNCTION: [Mature core protein]: 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 (By similarity). 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 (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 TNF-induced 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 (By similarity). Alters lipid metabolism by interacting
with hepatocellular proteins involved in lipid accumulation and storage
(By similarity). Induces up-regulation of FAS promoter activity, and
thereby contributes to the increased triglyceride accumulation in
hepatocytes (steatosis) (By similarity). {ECO:0000250|UniProtKB:P26662,
ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
ECO:0000250|UniProtKB:P29846, ECO:0000250|UniProtKB:Q99IB8,
ECO:0000305}.
-!- FUNCTION: [Envelope glycoprotein E1]: 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 (By similarity). 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 (By similarity). E1/E2 heterodimer
binds host apolipoproteins such as APOB and APOE thereby forming a
lipo-viro-particle (LVP) (By similarity). 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) (By similarity). The cholesterol
transfer activity of SCARB1 allows E2 exposure and binding of E2 to
SCARB1 and the tetraspanin CD81 (By similarity). E1/E2 heterodimer
binding on CD81 activates the epithelial growth factor receptor (EGFR)
signaling pathway (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
(By similarity). {ECO:0000250|UniProtKB:P27958}.
-!- FUNCTION: [Envelope glycoprotein E2]: 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 (By similarity). 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 (By similarity). The interaction
between envelope glycoprotein E2 and host apolipoprotein E/APOE allows
the proper assembly, maturation and infectivity of the viral particles
(By similarity). This interaction is probably promoted via the up-
regulation of cellular autophagy by the virus (By similarity). E1/E2
heterodimer binds host apolipoproteins such as APOB and APOE thereby
forming a lipo-viro-particle (LVP) (By similarity). 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) (By similarity). The
cholesterol transfer activity of SCARB1 allows E2 exposure and binding
of E2 to SCARB1 and the tetraspanin CD81 (By similarity). E1/E2
heterodimer binding on CD81 activates the epithelial growth factor
receptor (EGFR) signaling pathway (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 (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 dendritic cells (DCs), and on liver
sinusoidal endothelial cells and macrophage-like cells of lymph node
sinuses (By similarity). 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 (By similarity). The interaction between E2 and host
amino acid transporter complex formed by SLC3A2 and SLC7A5/LAT1 may
facilitate viral entry into host cell (By similarity).
{ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958}.
-!- FUNCTION: [Viroporin p7]: Ion channel protein that acts as a viroporin
and plays an essential role in the assembly, envelopment and secretion
of viral particles (By similarity). Regulates the host cell secretory
pathway, which induces the intracellular retention of viral
glycoproteins and favors assembly of viral particles (By similarity).
Creates a pore in acidic organelles and releases Ca(2+) and H(+) in the
cytoplasm of infected cells, leading to a productive viral infection
(By similarity). High levels of cytoplasmic Ca(2+) may trigger membrane
trafficking and transport of viral ER-associated proteins to
viroplasms, sites of viral genome replication (Probable). This ionic
imbalance induces the assembly of the inflammasome complex, which
triggers the maturation of pro-IL-1beta into IL-1beta through the
action of caspase-1 (By similarity). Targets also host mitochondria and
induces mitochondrial depolarization (By similarity). In addition of
its role as a viroporin, acts as a lipid raft adhesion factor (By
similarity). {ECO:0000250|UniProtKB:P27958,
ECO:0000250|UniProtKB:Q99IB8, ECO:0000305}.
-!- FUNCTION: [Protease NS2]: Cysteine protease required for the
proteolytic auto-cleavage between the non-structural proteins NS2 and
NS3 (By similarity). 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 (By similarity).
{ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P27958}.
-!- FUNCTION: [Serine protease/helicase NS3]: Displays three enzymatic
activities: serine protease with a chymotrypsin-like fold, NTPase and
RNA helicase (By similarity). NS3 serine protease, in association with
NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-
NS5A and NS5A-NS5B (By similarity). 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 (By similarity). 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 (By similarity). Binds a single ATP and catalyzes the unzipping
of a single base pair of dsRNA (By similarity). 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 (By similarity).
Cleaves host TICAM1/TRIF, thereby disrupting TLR3 signaling and
preventing the establishment of an antiviral state (By similarity).
{ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q9WMX2}.
-!- FUNCTION: [Non-structural protein 4B]: Induces a specific membrane
alteration that serves as a scaffold for the virus replication complex
(By similarity). This membrane alteration gives rise to the so-called
ER-derived membranous web that contains the replication complex (By
similarity). NS4B self-interaction contributes to its function in
membranous web formation (By similarity). Promotes host TRIF protein
degradation in a CASP8-dependent manner thereby inhibiting host TLR3-
mediated interferon signaling (By similarity). Disrupts the interaction
between STING and TBK1 contributing to the inhibition of interferon
signaling (By similarity). {ECO:0000250|UniProtKB:P27958}.
-!- FUNCTION: [Non-structural protein 5A]: 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 (By similarity). Zinc is
essential for RNA-binding (By similarity). Participates in the viral
particle production as a result of its interaction with the mature
viral 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 (By similarity). Prevents BIN1-induced apoptosis (By
similarity). 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 (By similarity).
Modulates TNFRSF21/DR6 signaling pathway for viral propagation (By
similarity). {ECO:0000250|UniProtKB:P26662,
ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
ECO:0000250|UniProtKB:Q99IB8, ECO:0000250|UniProtKB:Q9WMX2}.
-!- FUNCTION: [RNA-directed RNA polymerase]: RNA-dependent RNA polymerase
that performs primer-template recognition and RNA synthesis during
viral replication. {ECO:0000250|UniProtKB:P27958}.
-!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]:
Reaction=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'.; EC=3.4.21.98;
Evidence={ECO:0000250|UniProtKB:P27958};
-!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]:
Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-
diphosphate + H(+) + phosphate; Xref=Rhea:RHEA:23680,
ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474,
ChEBI:CHEBI:57930, ChEBI:CHEBI:61557; EC=3.6.1.15;
Evidence={ECO:0000250|UniProtKB:P27958};
-!- CATALYTIC ACTIVITY: [Serine protease/helicase NS3]:
Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13;
Evidence={ECO:0000250|UniProtKB:P27958};
-!- CATALYTIC ACTIVITY: [RNA-directed RNA polymerase]:
Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA-
COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395;
EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539,
ECO:0000269|PubMed:21209117};
-!- COFACTOR: [Protease NS2]:
Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
Evidence={ECO:0000250|UniProtKB:P26663};
Note=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). {ECO:0000250|UniProtKB:P26663};
-!- COFACTOR: [Serine protease/helicase NS3]:
Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
Evidence={ECO:0000250|UniProtKB:P26663};
Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
Evidence={ECO:0000250|UniProtKB:Q9WMX2};
Note=Binds 1 zinc ion, which has a structural role (By similarity). The
magnesium ion is essential for the helicase activity (By similarity).
{ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:Q9WMX2};
-!- COFACTOR: [RNA-directed RNA polymerase]:
Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
Evidence={ECO:0000250|UniProtKB:P26663};
Note=Binds 2 magnesium ion that constitute a dinuclear catalytic metal
center. {ECO:0000250|UniProtKB:P26663};
-!- ACTIVITY REGULATION: Inhibited by the antiviral drug hexamethylene
amiloride (By similarity). Inhibition by amantadine appears to be
genotype-dependent (By similarity). Also inhibited by long-alkyl-chain
iminosugar derivatives (By similarity). {ECO:0000250|UniProtKB:P26662,
ECO:0000250|UniProtKB:P27958}.
-!- ACTIVITY REGULATION: [RNA-directed RNA polymerase]: Activity is up-
regulated by PRK2/PKN2-mediated phosphorylation.
{ECO:0000250|UniProtKB:P27958}.
-!- SUBUNIT: [Mature core protein]: Homooligomer (By similarity). Interacts
with E1 (via C-terminus) (By similarity). 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 (By
similarity). Interacts with host STAT3; this interaction constitutively
activates STAT3 (By similarity). Interacts 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 (By similarity). Interacts
with host C1QR1 (By similarity). 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 with host EIF2AK2/PKR; 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).
{ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P26664,
ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:P29846,
ECO:0000250|UniProtKB:Q03463, ECO:0000250|UniProtKB:Q5EG65,
ECO:0000250|UniProtKB:Q99IB8}.
-!- SUBUNIT: [Envelope glycoprotein E1]: Forms a heterodimer with envelope
glycoprotein E2 (By similarity). Interacts with mature core protein (By
similarity). Interacts with protease NS2 (By similarity). The
heterodimer E1/E2 interacts with host CLDN1; this interaction plays a
role in viral entry into host cell (By similarity). Interacts with host
SPSB2 (via C-terminus) (By similarity). Part of the viral assembly
initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the
mature core protein (By similarity). {ECO:0000250|UniProtKB:P27958,
ECO:0000250|UniProtKB:Q99IB8}.
-!- SUBUNIT: [Envelope glycoprotein E2]: Forms a heterodimer with envelope
glycoprotein E1 (By similarity). Interacts with host CD81 and SCARB1
receptors; this interaction may play a role in viral entry into host
cell (By similarity). Interacts with host EIF2AK2/PKR; this interaction
inhibits EIF2AK2 and probably allows the virus to evade the innate
immune response (By similarity). Interacts with host CD209/DC-SIGN and
CLEC4M/DC-SIGNR (By similarity). Interact with host SPCS1; this
interaction is essential for viral particle assembly (By similarity).
Interacts with protease NS2 (By similarity). The heterodimer E1/E2
interacts with host CLDN1; this interaction plays a role in viral entry
into host cell (By similarity). 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 (By similarity).
Interacts with human PLSCR1 (By similarity).
{ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8,
ECO:0000250|UniProtKB:Q9WMX2}.
-!- SUBUNIT: [Viroporin p7]: Homohexamer (By similarity). Homoheptamer (By
similarity). Interacts with protease NS2 (By similarity).
{ECO:0000250|UniProtKB:O92972, ECO:0000250|UniProtKB:P27958,
ECO:0000250|UniProtKB:Q99IB8}.
-!- SUBUNIT: [Protease NS2]: Homodimer (By similarity). Interacts with host
SPCS1; this interaction is essential for viral particle assembly (By
similarity). Interacts with envelope glycoprotein E1 (By similarity).
Interacts with envelope glycoprotein E2 (By similarity). Interacts with
viroporin p7 (By similarity). Interacts with serine protease/helicase
NS3 (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 (By similarity). Part of the viral
assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A
and the mature core protein (By similarity).
{ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8}.
-!- SUBUNIT: [Serine protease/helicase NS3]: Interacts with protease NS2
(By similarity). 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 (By similarity). 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 (By similarity). Interacts with host TICAM1;
this interaction leads to the cleavage and inhibition of host TICAM1
(By similarity). 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 (By
similarity). Part of the viral assembly initiation complex composed of
NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By
similarity). {ECO:0000250|UniProtKB:P26663,
ECO:0000250|UniProtKB:P27958, ECO:0000250|UniProtKB:Q99IB8,
ECO:0000250|UniProtKB:Q9WMX2}.
-!- SUBUNIT: [Non-structural protein 4A]: Interacts with NS3 serine
protease; 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 (By similarity).
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 (By similarity). Part of the viral assembly
initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the
mature core protein (By similarity). {ECO:0000250|UniProtKB:P26662,
ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P27958,
ECO:0000250|UniProtKB:Q99IB8}.
-!- SUBUNIT: [Non-structural protein 4B]: Homomultimer (By similarity).
Interacts with non-structural protein NS5A (By similarity). 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 (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 (By similarity). {ECO:0000250|UniProtKB:P27958,
ECO:0000250|UniProtKB:Q99IB8}.
-!- SUBUNIT: [Non-structural protein 5A]: Monomer (By similarity).
Homodimer; dimerization is required for RNA-binding (By similarity).
Interacts with mature core protein (By similarity). Interacts (via N-
terminus) with non-structural protein 4A (By similarity). Interacts
with non-structural protein 4B (By similarity). Interacts with RNA-
directed RNA polymerase (By similarity). 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 (By similarity). Interacts with host GRB2 (By similarity).
Interacts with host BIN1 (By similarity). Interacts with host PIK3R1
(By similarity). Interacts with host SRCAP (By similarity). Interacts
with host FKBP8 (By similarity). Interacts with host VAPB (By
similarity). 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 (By similarity). 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 (By
similarity). 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 (By similarity).
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 (By
similarity). Interacts (via N-terminus) with host CIDEB (via N-
terminus); this interaction seems to regulate the association of HCV
particles with APOE (By similarity). 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 (By similarity). Interacts with
host RAB18; this interaction may promote the association of NS5A and
other replicase components with lipid droplets (By similarity).
{ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P26663,
ECO:0000250|UniProtKB:P26664, ECO:0000250|UniProtKB:P27958,
ECO:0000250|UniProtKB:Q99IB8}.
-!- SUBUNIT: [RNA-directed RNA polymerase]: Homooligomer (By similarity).
Interacts with non-structural protein 5A (By similarity). Interacts
with host VAPB (By similarity). Interacts with host PRK2/PKN2 (By
similarity). Interacts with host HNRNPA1 and SEPT6; these interactions
facilitate viral replication (By similarity). Part of the replication
complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA
polymerase (By similarity). {ECO:0000250|UniProtKB:P27958}.
-!- INTERACTION:
PRO_0000037615; PRO_0000037566 [P27958]; Xeno; NbExp=4; IntAct=EBI-6875462, EBI-6377335;
-!- SUBCELLULAR LOCATION: [Core protein precursor]: Host endoplasmic
reticulum membrane {ECO:0000250|UniProtKB:P26664}; Single-pass membrane
protein {ECO:0000255}. Host mitochondrion membrane
{ECO:0000250|UniProtKB:P26664}; Single-pass type I membrane protein
{ECO:0000255}. Note=The C-terminal transmembrane domain of the core
protein precursor contains an ER signal leading the nascent polyprotein
to the ER membrane.
-!- SUBCELLULAR LOCATION: [Mature core protein]: Virion
{ECO:0000250|UniProtKB:Q99IB8}. Host cytoplasm
{ECO:0000250|UniProtKB:Q99IB8}. Host nucleus
{ECO:0000250|UniProtKB:P26662}. Host lipid droplet
{ECO:0000250|UniProtKB:Q99IB8}. Note=Only a minor proportion of core
protein is present in the nucleus (By similarity). Probably present on
the surface of lipid droplets (By similarity).
{ECO:0000250|UniProtKB:P27958}.
-!- SUBCELLULAR LOCATION: [Envelope glycoprotein E1]: Virion membrane
{ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host
endoplasmic reticulum membrane; Single-pass type I membrane protein
{ECO:0000250|UniProtKB:P27958}. Note=The C-terminal transmembrane
domain acts as a signal sequence and forms a hairpin structure before
cleavage by host signal peptidase (By similarity). After cleavage, the
membrane sequence is retained at the C-terminus of the protein, serving
as ER membrane anchor (By similarity). A reorientation of the second
hydrophobic stretch occurs after cleavage producing a single reoriented
transmembrane domain (By similarity). These events explain the final
topology of the protein (By similarity).
{ECO:0000250|UniProtKB:P27958}.
-!- SUBCELLULAR LOCATION: [Envelope glycoprotein E2]: Virion membrane
{ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host
endoplasmic reticulum membrane; Single-pass type I membrane protein
{ECO:0000250|UniProtKB:P27958}. Host lipid droplet
{ECO:0000250|UniProtKB:Q9WMX2}. Note=The C-terminal transmembrane
domain acts as a signal sequence and forms a hairpin structure before
cleavage by host signal peptidase (By similarity). After cleavage, the
membrane sequence is retained at the C-terminus of the protein, serving
as ER membrane anchor (By similarity). A reorientation of the second
hydrophobic stretch occurs after cleavage producing a single reoriented
transmembrane domain (By similarity). These events explain the final
topology of the protein (By similarity).
{ECO:0000250|UniProtKB:P27958}.
-!- SUBCELLULAR LOCATION: [Viroporin p7]: Host endoplasmic reticulum
membrane {ECO:0000250|UniProtKB:P27958}; Multi-pass membrane protein
{ECO:0000250|UniProtKB:P27958}. Host mitochondrion
{ECO:0000250|UniProtKB:P27958}. Host cell membrane
{ECO:0000250|UniProtKB:P27958}. Note=The C-terminus of p7 membrane
domain acts as a signal sequence (By similarity). After cleavage by
host signal peptidase, the membrane sequence is retained at the C-
terminus of the protein, serving as ER membrane anchor (By similarity).
ER retention of p7 is leaky and a small fraction reaches the plasma
membrane (By similarity). {ECO:0000250|UniProtKB:P27958}.
-!- SUBCELLULAR LOCATION: [Protease NS2]: Host endoplasmic reticulum
membrane {ECO:0000250|UniProtKB:P27958}; Multi-pass membrane protein
{ECO:0000250|UniProtKB:P27958}. Host lipid droplet
{ECO:0000250|UniProtKB:Q9WMX2}. Note=Probably present on the surface of
lipid droplets. {ECO:0000250|UniProtKB:Q99IB8}.
-!- SUBCELLULAR LOCATION: [Serine protease/helicase NS3]: Host endoplasmic
reticulum membrane {ECO:0000305}; Peripheral membrane protein
{ECO:0000305}. Note=NS3 is associated to the ER membrane through its
binding to NS4A. {ECO:0000305}.
-!- SUBCELLULAR LOCATION: [Non-structural protein 4A]: Host endoplasmic
reticulum membrane {ECO:0000305}; Single-pass type I membrane protein
{ECO:0000305}. Note=Host membrane insertion occurs after processing by
the NS3 protease.
-!- SUBCELLULAR LOCATION: [Non-structural protein 4B]: Host endoplasmic
reticulum membrane {ECO:0000250|UniProtKB:P27958}; Multi-pass membrane
protein {ECO:0000250|UniProtKB:P27958}. Note=A reorientation of the N-
terminus into the ER lumen occurs post-translationally.
{ECO:0000250|UniProtKB:P27958}.
-!- SUBCELLULAR LOCATION: [Non-structural protein 5A]: Host endoplasmic
reticulum membrane {ECO:0000250|UniProtKB:P27958}; Peripheral membrane
protein {ECO:0000250|UniProtKB:P27958}. Host cytoplasm, host
perinuclear region {ECO:0000250|UniProtKB:P27958}. Host mitochondrion
{ECO:0000250|UniProtKB:P26662}. Host cytoplasm
{ECO:0000250|UniProtKB:P27958}. Host nucleus
{ECO:0000250|UniProtKB:P26662}. Host lipid droplet
{ECO:0000250|UniProtKB:Q9WMX2}. Note=Host membrane insertion occurs
after processing by the NS3 protease (By similarity). Localizes at the
surface of lipid droplets (By similarity).
{ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P27958}.
-!- SUBCELLULAR LOCATION: [RNA-directed RNA polymerase]: Host cytoplasm
{ECO:0000250|UniProtKB:P27958}. Host endoplasmic reticulum membrane;
Single-pass type IV membrane protein {ECO:0000250|UniProtKB:P27958}.
Note=Host membrane insertion occurs after processing by the NS3
protease. {ECO:0000250|UniProtKB:P27958}.
-!- DOMAIN: [Envelope glycoprotein E1]: The transmembrane regions of
envelope E1 and E2 glycoproteins are involved in heterodimer formation,
ER localization, and assembly of these proteins.
{ECO:0000250|UniProtKB:P27958}.
-!- DOMAIN: [Envelope glycoprotein E2]: The transmembrane regions of
envelope E1 and E2 glycoproteins are involved in heterodimer formation,
ER localization, and assembly of these proteins (By similarity).
Envelope E2 glycoprotein contain two highly variable regions called
hypervariable region 1 and 2 (HVR1 and HVR2) (By similarity). E2 also
contain two segments involved in CD81-binding (By similarity). HVR1 is
implicated in the SCARB1-mediated cell entry and probably acts as a
regulator of the association of particles with lipids (By similarity).
{ECO:0000250|UniProtKB:P26663, ECO:0000250|UniProtKB:P27958}.
-!- DOMAIN: [Protease NS2]: The N-terminus of NS3 is required for the
catalytic activity of protease NS2 (By similarity). The minimal
catalytic region includes the C-terminus of NS2 and the N-terminus NS3
protease domain (active region NS2-3) (By similarity).
{ECO:0000250|UniProtKB:P26663}.
-!- DOMAIN: [Serine protease/helicase NS3]: The N-terminal one-third
contains the protease activity (By similarity). This region contains a
zinc atom that does not belong to the active site, but may play a
structural rather than a catalytic role (By similarity). This region is
essential for the activity of protease NS2, maybe by contributing to
the folding of the latter (By similarity). The NTPase/helicase activity
is located in the twothirds C-terminus of NS3, this domain contains the
NTPase and RNA-binding regions (By similarity).
{ECO:0000250|UniProtKB:P26662, ECO:0000250|UniProtKB:P26663,
ECO:0000250|UniProtKB:P27958}.
-!- DOMAIN: [Non-structural protein 4B]: Contains a glycine zipper region
that critically contributes to the biogenesis of functional ER-derived
replication organelles. {ECO:0000250|UniProtKB:Q99IB8}.
-!- DOMAIN: [Non-structural protein 5A]: The N-terminus of NS5A acts as
membrane anchor (By similarity). The central part of NS5A contains a
variable region called interferon sensitivity determining region (ISDR)
and seems to be intrinsically disordered and interacts with NS5B and
host EIF2AK2 (By similarity). The C-terminus of NS5A contains a
variable region called variable region 3 (V3) (By similarity). ISDR and
V3 may be involved in sensitivity and/or resistance to IFN-alpha
therapy (By similarity). The C-terminus contains a nuclear localization
signal (By similarity). The SH3-binding domain is involved in the
interaction with host BIN1, GRB2 and Src-family kinases (By
similarity). {ECO:0000250|UniProtKB:P26662,
ECO:0000250|UniProtKB:P27958}.
-!- PTM: [Genome polyprotein]: Specific enzymatic cleavages in vivo yield
mature proteins (By similarity). The structural proteins, core, E1, E2
and p7 are produced by proteolytic processing by host signal peptidases
(By similarity). 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 (By similarity).
Autoprocessing between NS2 and NS3 is mediated by the NS2 cysteine
protease catalytic domain and regulated by the NS3 N-terminal domain
(By similarity). {ECO:0000250|UniProtKB:P26664,
ECO:0000250|UniProtKB:P27958}.
-!- PTM: [Mature core protein]: Phosphorylated by host PKC and PKA.
{ECO:0000250|UniProtKB:Q01403}.
-!- PTM: [Mature core protein]: Ubiquitinated; mediated by UBE3A and
leading to core protein subsequent proteasomal degradation.
{ECO:0000250|UniProtKB:Q03463}.
-!- PTM: [Envelope glycoprotein E1]: Highly N-glycosylated.
{ECO:0000250|UniProtKB:P27958}.
-!- PTM: [Envelope glycoprotein E2]: Highly N-glycosylated.
{ECO:0000250|UniProtKB:P27958}.
-!- PTM: [Protease NS2]: Palmitoylation is required for NS2/3
autoprocessing and E2 recruitment to membranes.
{ECO:0000250|UniProtKB:P27958}.
-!- PTM: [Non-structural protein 4B]: Palmitoylated. This modification may
play a role in its polymerization or in protein-protein interactions.
{ECO:0000250|UniProtKB:P27958}.
-!- PTM: [Non-structural protein 5A]: 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 or
RPS6KB1 kinases may be responsible for NS5A phosphorylation (By
similarity). {ECO:0000250|UniProtKB:P26662,
ECO:0000250|UniProtKB:P26664}.
-!- PTM: [Non-structural protein 5A]: Tyrosine phosphorylation is essential
for the interaction with host SRC. {ECO:0000250|UniProtKB:Q99IB8}.
-!- PTM: [RNA-directed RNA polymerase]: The N-terminus is phosphorylated by
host PRK2/PKN2. {ECO:0000250|UniProtKB:P26662}.
-!- 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. {ECO:0000305}.
-!- MISCELLANEOUS: [Non-structural protein 5A]: Cell culture adaptation of
the virus leads to mutations in NS5A, reducing its inhibitory effect on
replication. {ECO:0000305}.
-!- MISCELLANEOUS: [Mature 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.
{ECO:0000250|UniProtKB:P26662}.
-!- SIMILARITY: Belongs to the hepacivirus polyprotein family.
{ECO:0000305}.
-!- 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. {ECO:0000305}.
-!- WEB RESOURCE: Name=Virus Pathogen Resource;
URL="https://www.viprbrc.org/brc/home.spg?decorator=flavi_hcv";
---------------------------------------------------------------------------
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EMBL; D00944; BAA00792.1; -; Genomic_RNA.
PIR; JQ1303; JQ1303.
PDB; 1YUY; X-ray; 1.90 A; A=2443-3012.
PDB; 1YV2; X-ray; 2.50 A; A=2443-3012.
PDB; 1YVX; X-ray; 2.00 A; A=2443-3012.
PDB; 1YVZ; X-ray; 2.20 A; A=2443-3012.
PDB; 2XWH; X-ray; 1.80 A; A=2443-3005.
PDB; 4ADP; X-ray; 1.90 A; A=2443-3012.
PDBsum; 1YUY; -.
PDBsum; 1YV2; -.
PDBsum; 1YVX; -.
PDBsum; 1YVZ; -.
PDBsum; 2XWH; -.
PDBsum; 4ADP; -.
BMRB; P26660; -.
SMR; P26660; -.
IntAct; P26660; 7.
BindingDB; P26660; -.
DrugBank; DB03388; 3-[(2,4-Dichlorobenzoyl)(Isopropyl)Amino]-5-Phenylthiophene-2-Carboxylic Acid.
DrugBank; DB03647; 3-[Isopropyl(4-Methylbenzoyl)Amino]-5-Phenylthiophene-2-Carboxylic Acid.
MEROPS; S29.001; -.
PRIDE; P26660; -.
ABCD; P26660; 1 sequenced antibody.
euHCVdb; D00944; -.
EvolutionaryTrace; P26660; -.
Proteomes; UP000002682; Genome.
GO; GO:0044167; C:host cell endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
GO; GO:0044186; C:host cell lipid droplet; IEA:UniProtKB-SubCell.
GO; GO:0044191; C:host cell mitochondrial membrane; IEA:UniProtKB-SubCell.
GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
GO; GO:0044385; C:integral to membrane of host cell; IEA:UniProtKB-KW.
GO; GO:0019031; C:viral envelope; IEA:UniProtKB-KW.
GO; GO:0019013; C:viral nucleocapsid; IEA:UniProtKB-KW.
GO; GO:0055036; C:virion membrane; IEA:UniProtKB-SubCell.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0140603; F:ATP hydrolysis activity; IEA:RHEA.
GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro.
GO; GO:0005216; F:ion channel activity; IEA:UniProtKB-KW.
GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
GO; GO:0003724; F:RNA helicase activity; IEA:UniProtKB-EC.
GO; GO:0003968; F:RNA-directed 5'-3' RNA polymerase activity; IEA:UniProtKB-KW.
GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro.
GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
GO; GO:0075512; P:clathrin-dependent endocytosis of virus by host cell; IEA:UniProtKB-KW.
GO; GO:0039654; P:fusion of virus membrane with host endosome membrane; IEA:UniProtKB-KW.
GO; GO:0039520; P:induction by virus of host autophagy; IEA:UniProtKB-KW.
GO; GO:0039645; P:modulation by virus of host G1/S transition checkpoint; IEA:UniProtKB-KW.
GO; GO:0039707; P:pore formation by virus in membrane of host cell; IEA:UniProtKB-KW.
GO; GO:0051259; P:protein complex oligomerization; IEA:UniProtKB-KW.
GO; GO:0039545; P:suppression by virus of host MAVS activity; IEA:UniProtKB-KW.
GO; GO:0039563; P:suppression by virus of host STAT1 activity; IEA:UniProtKB-KW.
GO; GO:0039547; P:suppression by virus of host TRAF activity; IEA:UniProtKB-KW.
GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
GO; GO:0019087; P:transformation of host cell by virus; IEA:InterPro.
GO; GO:0016032; P:viral process; IMP:CACAO.
GO; GO:0039694; P:viral RNA genome replication; IEA:InterPro.
GO; GO:0019062; P:virion attachment to host cell; IEA:UniProtKB-KW.
Gene3D; 1.20.1280.150; -; 1.
Gene3D; 2.20.25.210; -; 1.
Gene3D; 2.20.25.220; -; 1.
Gene3D; 2.30.30.710; -; 1.
Gene3D; 2.40.10.10; -; 1.
Gene3D; 3.30.70.270; -; 2.
Gene3D; 3.40.50.300; -; 2.
InterPro; IPR011492; DEAD_Flavivir.
InterPro; IPR043502; DNA/RNA_pol_sf.
InterPro; IPR002521; HCV_core_C.
InterPro; IPR002522; HCV_core_N.
InterPro; IPR002519; HCV_env.
InterPro; IPR002531; HCV_NS1.
InterPro; IPR002518; HCV_NS2.
InterPro; IPR042205; HCV_NS2_C.
InterPro; IPR042209; HCV_NS2_N.
InterPro; IPR000745; HCV_NS4a.
InterPro; IPR001490; HCV_NS4b.
InterPro; IPR002868; HCV_NS5a.
InterPro; IPR013193; HCV_NS5a_1B_dom.
InterPro; IPR038568; HCV_NS5A_1B_sf.
InterPro; IPR024350; HCV_NS5a_C.
InterPro; IPR014001; Helicase_ATP-bd.
InterPro; IPR001650; Helicase_C.
InterPro; IPR013192; NS5A_1a.
InterPro; IPR038170; NS5A_1a_sf.
InterPro; IPR027417; P-loop_NTPase.
InterPro; IPR009003; Peptidase_S1_PA.
InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
InterPro; IPR004109; Peptidase_S29_NS3.
InterPro; IPR043128; Rev_trsase/Diguanyl_cyclase.
InterPro; IPR007094; RNA-dir_pol_PSvirus.
InterPro; IPR002166; RNA_pol_HCV.
Pfam; PF07652; Flavi_DEAD; 1.
Pfam; PF01543; HCV_capsid; 1.
Pfam; PF01542; HCV_core; 1.
Pfam; PF01539; HCV_env; 1.
Pfam; PF01560; HCV_NS1; 1.
Pfam; PF01538; HCV_NS2; 1.
Pfam; PF01006; HCV_NS4a; 1.
Pfam; PF01001; HCV_NS4b; 1.
Pfam; PF01506; HCV_NS5a; 1.
Pfam; PF08300; HCV_NS5a_1a; 1.
Pfam; PF08301; HCV_NS5a_1b; 1.
Pfam; PF12941; HCV_NS5a_C; 1.
Pfam; PF02907; Peptidase_S29; 1.
Pfam; PF00998; RdRP_3; 1.
SMART; SM00487; DEXDc; 1.
SMART; SM00490; HELICc; 1.
SUPFAM; SSF50494; SSF50494; 1.
SUPFAM; SSF52540; SSF52540; 2.
SUPFAM; SSF56672; SSF56672; 1.
PROSITE; PS51693; HCV_NS2_PRO; 1.
PROSITE; PS51192; HELICASE_ATP_BIND_1; 1.
PROSITE; PS51194; HELICASE_CTER; 1.
PROSITE; PS51822; HV_PV_NS3_PRO; 1.
PROSITE; PS50507; RDRP_SSRNA_POS; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Activation of host autophagy by virus;
Apoptosis; ATP-binding; Capsid protein;
Clathrin-mediated endocytosis of virus by host; Disulfide bond;
Fusion of virus membrane with host endosomal membrane;
Fusion of virus membrane with host membrane;
G1/S host cell cycle checkpoint dysregulation by virus; Glycoprotein;
Helicase; Host cell membrane; Host cytoplasm; Host endoplasmic reticulum;
Host lipid droplet; Host membrane; Host mitochondrion; Host nucleus;
Host-virus interaction; Hydrolase;
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 channel; Ion transport;
Isopeptide bond; Lipoprotein; Magnesium; Membrane; Metal-binding;
Modulation of host cell cycle by virus; Multifunctional enzyme;
Nucleotide-binding; Nucleotidyltransferase; Oncogene; Palmitate;
Phosphoprotein; Protease; Ribonucleoprotein; RNA-binding;
RNA-directed RNA polymerase; Serine protease; Thiol protease;
Transcription; Transcription regulation; Transferase; Transmembrane;
Transmembrane helix; Transport; Ubl conjugation;
Viral attachment to host cell; Viral envelope protein; Viral immunoevasion;
Viral ion channel; Viral nucleoprotein;
Viral penetration into host cytoplasm; Viral RNA replication; Virion;
Virus endocytosis by host; Virus entry into host cell; Zinc.
INIT_MET 1
/note="Removed; by host"
/evidence="ECO:0000250|UniProtKB:P26664"
CHAIN 2..3033
/note="Genome polyprotein"
/id="PRO_0000450914"
CHAIN 2..191
/note="Core protein precursor"
/id="PRO_0000037608"
CHAIN 2..177
/note="Mature core protein"
/id="PRO_0000037609"
PROPEP 178..191
/note="ER anchor for the core protein, removed in mature
form by host signal peptidase"
/id="PRO_0000037610"
CHAIN 192..383
/note="Envelope glycoprotein E1"
/id="PRO_0000037611"
CHAIN 384..750
/note="Envelope glycoprotein E2"
/id="PRO_0000037612"
CHAIN 751..813
/note="Viroporin p7"
/id="PRO_0000037613"
CHAIN 814..1030
/note="Protease NS2"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
/id="PRO_0000037614"
CHAIN 1031..1661
/note="Serine protease/helicase NS3"
/id="PRO_0000037615"
CHAIN 1662..1715
/note="Non-structural protein 4A"
/id="PRO_0000037616"
CHAIN 1716..1976
/note="Non-structural protein 4B"
/id="PRO_0000037617"
CHAIN 1977..2442
/note="Non-structural protein 5A"
/id="PRO_0000037618"
CHAIN 2443..3033
/note="RNA-directed RNA polymerase"
/id="PRO_0000037619"
TOPO_DOM 2..168
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 169..189
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 190..358
/note="Lumenal"
/evidence="ECO:0000250|UniProtKB:P27958"
TRANSMEM 359..379
/note="Helical"
/evidence="ECO:0000250|UniProtKB:P27958"
TOPO_DOM 380..729
/note="Lumenal"
/evidence="ECO:0000250|UniProtKB:P27958"
TRANSMEM 730..750
/note="Helical"
/evidence="ECO:0000250|UniProtKB:P27958"
TOPO_DOM 751..761
/note="Lumenal"
/evidence="ECO:0000250|UniProtKB:P27958"
TRANSMEM 762..782
/note="Helical"
/evidence="ECO:0000250|UniProtKB:P27958"
TOPO_DOM 783..786
/note="Cytoplasmic"
/evidence="ECO:0000250|UniProtKB:P27958"
TRANSMEM 787..807
/note="Helical"
/evidence="ECO:0000250|UniProtKB:P27958"
TOPO_DOM 808..817
/note="Lumenal"
/evidence="ECO:0000250|UniProtKB:P27958"
TRANSMEM 818..838
/note="Helical"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
TOPO_DOM 839..885
/note="Cytoplasmic"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
TRANSMEM 886..906
/note="Helical"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
TOPO_DOM 907..932
/note="Lumenal"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
TRANSMEM 933..953
/note="Helical"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
TOPO_DOM 954..1661
/note="Cytoplasmic"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
TRANSMEM 1662..1682
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1683..1809
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 1810..1830
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1831..1832
/note="Lumenal"
/evidence="ECO:0000250|UniProtKB:P27958"
TRANSMEM 1833..1853
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1854
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 1855..1875
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1876..1885
/note="Lumenal"
/evidence="ECO:0000255"
TRANSMEM 1886..1906
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1907..1976
/note="Cytoplasmic"
/evidence="ECO:0000255"
INTRAMEM 1977..2007
/evidence="ECO:0000250|UniProtKB:P27958"
TOPO_DOM 2008..3012
/note="Cytoplasmic"
/evidence="ECO:0000250|UniProtKB:P27958"
TRANSMEM 3013..3033
/note="Helical"
/evidence="ECO:0000250|UniProtKB:P27958"
DOMAIN 907..1030
/note="Peptidase C18"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
DOMAIN 1031..1212
/note="Peptidase S29"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
DOMAIN 1221..1373
/note="Helicase ATP-binding"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
DOMAIN 2656..2774
/note="RdRp catalytic"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
NP_BIND 1234..1241
/note="ATP"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
REGION 2..75
/note="Disordered"
/evidence="ECO:0000250|UniProtKB:P27958"
REGION 2..59
/note="Interaction with DDX3X"
/evidence="ECO:0000250|UniProtKB:Q5EG65"
REGION 2..58
/note="Interaction with EIF2AK2/PKR"
/evidence="ECO:0000250|UniProtKB:P26662"
REGION 2..23
/note="Interaction with STAT1"
/evidence="ECO:0000250|UniProtKB:P26662"
REGION 112..152
/note="Important for endoplasmic reticulum and
mitochondrial localization"
/evidence="ECO:0000250|UniProtKB:P26662"
REGION 122..173
/note="Interaction with APOA2"
/evidence="ECO:0000250|UniProtKB:P29846"
REGION 164..167
/note="Important for lipid droplets localization"
/evidence="ECO:0000250|UniProtKB:P27958"
REGION 265..296
/note="Important for fusion"
/evidence="ECO:0000250|UniProtKB:P27958"
REGION 385..411
/note="HVR1"
/evidence="ECO:0000250|UniProtKB:P27958"
REGION 484..496
/note="CD81-binding 1"
/evidence="ECO:0000250|UniProtKB:P26663"
REGION 524..555
/note="CD81-binding 2"
/evidence="ECO:0000250|UniProtKB:P26663"
REGION 664..675
/note="EIF2AK2/eIF2-alpha phosphorylation homology domain
(PePHD)"
REGION 908..1210
/note="Protease NS2-3"
/evidence="ECO:0000250|UniProtKB:P26663"
REGION 933..953
/note="Interaction with host SCPS1"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
REGION 1490..1501
/note="RNA-binding"
/evidence="ECO:0000250|UniProtKB:P26663"
REGION 1683..1694
/note="NS3-binding"
/evidence="ECO:0000250|UniProtKB:P27958"
REGION 1837..1865
/note="Glycine zipper"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
REGION 1982..2002
/note="Membrane-binding"
/evidence="ECO:0000250|UniProtKB:P27958"
REGION 2009..2225
/note="RNA-binding"
/evidence="ECO:0000250|UniProtKB:P27958"
REGION 2124..2332
/note="Transcriptional activation"
/evidence="ECO:0000255"
REGION 2124..2212
/note="FKBP8-binding"
/evidence="ECO:0000250|UniProtKB:P26662"
REGION 2139..2143
/note="Interaction with non-structural protein 4A"
/evidence="ECO:0000250|UniProtKB:P26662"
REGION 2193..2214
/note="Disordered"
/evidence="ECO:0000256|SAM:MobiDB-lite"
REGION 2210..2249
/note="ISDR"
/evidence="ECO:0000250|UniProtKB:P26662"
REGION 2214..2275
/note="Interaction with EIF2AK2/PKR"
/evidence="ECO:0000250|UniProtKB:P26663"
REGION 2253..2310
/note="NS4B-binding"
/evidence="ECO:0000255"
REGION 2309..2335
/note="Disordered"
/evidence="ECO:0000256|SAM:MobiDB-lite"
REGION 2336..2447
/note="Interaction with host IFI27"
/evidence="ECO:0000250|UniProtKB:P27958"
REGION 2351..2431
/note="Disordered"
/evidence="ECO:0000256|SAM:MobiDB-lite"
REGION 2358..2381
/note="V3"
MOTIF 5..13
/note="Nuclear localization signal"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOTIF 38..43
/note="Nuclear localization signal"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOTIF 58..64
/note="Nuclear localization signal"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOTIF 66..71
/note="Nuclear localization signal"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOTIF 1320..1323
/note="DECH box"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOTIF 2322..2325
/note="SH3-binding"
/evidence="ECO:0000255"
MOTIF 2326..2334
/note="Nuclear localization signal"
/evidence="ECO:0000250|UniProtKB:P26662"
COMPBIAS 47..74
/note="Basic and acidic residues"
/evidence="ECO:0000256|SAM:MobiDB-lite"
COMPBIAS 2199..2214
/note="Polar residues"
/evidence="ECO:0000256|SAM:MobiDB-lite"
COMPBIAS 2357..2371
/note="Polar residues"
/evidence="ECO:0000256|SAM:MobiDB-lite"
ACT_SITE 956
/note="For protease NS2 activity; shared with dimeric
partner"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
ACT_SITE 976
/note="For protease NS2 activity; shared with dimeric
partner"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
ACT_SITE 997
/note="For protease NS2 activity; shared with dimeric
partner"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
ACT_SITE 1087
/note="Charge relay system; for serine protease NS3
activity"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
ACT_SITE 1111
/note="Charge relay system; for serine protease NS3
activity"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
ACT_SITE 1169
/note="Charge relay system; for serine protease NS3
activity"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1127
/note="Zinc; structural"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1129
/note="Zinc; structural"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1175
/note="Zinc; structural"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1179
/note="Zinc; structural"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1241
/note="Magnesium; catalytic; for NS3 helicase activity"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
METAL 1321
/note="Magnesium; catalytic; for NS3 helicase activity"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
METAL 2015
/note="Zinc; structural"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
METAL 2033
/note="Zinc; structural"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
METAL 2035
/note="Zinc; structural"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
METAL 2056
/note="Zinc; structural"
/evidence="ECO:0000250|UniProtKB:Q9WMX2"
METAL 2662
/note="Magnesium; catalytic; for RNA-directed RNA
polymerase activity"
/evidence="ECO:0000250|UniProtKB:P26663"
METAL 2760
/note="Magnesium; catalytic; for RNA-directed RNA
polymerase activity"
/evidence="ECO:0000250|UniProtKB:P26663"
METAL 2761
/note="Magnesium; catalytic; for RNA-directed RNA
polymerase activity"
/evidence="ECO:0000250|UniProtKB:P26663"
SITE 177..178
/note="Cleavage; by host signal peptide peptidase"
/evidence="ECO:0000250|UniProtKB:P26662"
SITE 191..192
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000250|UniProtKB:P26662"
SITE 383..384
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000250|UniProtKB:P26662"
SITE 750..751
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000250"
SITE 813..814
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000250"
SITE 1030..1031
/note="Cleavage; by protease NS2"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
SITE 1661..1662
/note="Cleavage; ; by serine protease/helicase NS3"
/evidence="ECO:0000250|UniProtKB:P27958"
SITE 1715..1716
/note="Cleavage; ; by serine protease/helicase NS3"
/evidence="ECO:0000250|UniProtKB:P27958"
SITE 1976..1977
/note="Cleavage; by serine protease/helicase NS3"
/evidence="ECO:0000250|UniProtKB:P27958"
SITE 2442..2443
/note="Cleavage; by serine protease/helicase NS3"
/evidence="ECO:0000250|UniProtKB:P27958"
MOD_RES 2
/note="N-acetylserine; by host"
/evidence="ECO:0000250|UniProtKB:Q913V3"
MOD_RES 53
/note="Phosphoserine; by host"
/evidence="ECO:0000250|UniProtKB:Q01403"
MOD_RES 99
/note="Phosphoserine; by host"
/evidence="ECO:0000250|UniProtKB:Q01403"
MOD_RES 116
/note="Phosphoserine; by host PKA"
/evidence="ECO:0000250|UniProtKB:Q01403"
MOD_RES 2069
/note="Phosphotyrosine; by host"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOD_RES 2198
/note="Phosphoserine; by host; in p56"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOD_RES 2201
/note="Phosphoserine; by host; in p58"
/evidence="ECO:0000250|UniProtKB:P26662"
MOD_RES 2205
/note="Phosphoserine; by host; in p56 and p58, regulates
intracellular NS5A distribution"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOD_RES 2208
/note="Phosphoserine; by host; in p58"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOD_RES 2211
/note="Phosphoserine; by host; in p58"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOD_RES 2214
/note="Phosphoserine; by host; in p58"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
MOD_RES 2324
/note="Phosphothreonine; by host"
/evidence="ECO:0000250|UniProtKB:Q99IB8"
LIPID 926
/note="S-palmitoyl cysteine; by host"
/evidence="ECO:0000250|UniProtKB:P27958"
LIPID 1972
/note="S-palmitoyl cysteine; by host"
/evidence="ECO:0000250|UniProtKB:P27958"
LIPID 1976
/note="S-palmitoyl cysteine; by host; partial"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 196
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 209
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 234
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 305
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 417
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 423
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 430
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 448
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 477
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 534
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 542
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 558
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 578
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 627
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
CARBOHYD 649
/note="N-linked (GlcNAc...) (high mannose) asparagine; by
host"
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 429..554
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 452..459
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 488..496
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 505..510
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 566..571
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 585..589
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 601..624
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 611..648
/evidence="ECO:0000250|UniProtKB:P27958"
DISULFID 656..681
/evidence="ECO:0000250|UniProtKB:P27958"
CROSSLNK 2350
/note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
G-Cter in ubiquitin)"
/evidence="ECO:0000250|UniProtKB:P27958"
MUTAGEN 2847
/note="V->I: Improves RdRp dinucleotide synthesis and de
novo RNA synthesis efficiency at the transition-to-
elongation step."
/evidence="ECO:0000269|PubMed:22532694"
STRAND 2444..2448
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2467..2470
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2476..2478
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2479..2481
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2484..2486
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2487..2494
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2504..2517
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2527..2532
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2542..2544
/evidence="ECO:0007829|PDB:1YUY"
HELIX 2547..2551
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2555..2570
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2572..2574
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2578..2582
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2586..2588
/evidence="ECO:0007829|PDB:2XWH"
TURN 2591..2593
/evidence="ECO:0007829|PDB:4ADP"
STRAND 2601..2604
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2607..2629
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2630..2632
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2634..2636
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2639..2652
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2653..2661
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2666..2669
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2672..2682
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2689..2701
/evidence="ECO:0007829|PDB:2XWH"
TURN 2702..2704
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2706..2709
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2715..2719
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2728..2748
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2751..2758
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2761..2767
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2771..2787
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2792..2794
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2802..2804
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2810..2816
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2822..2828
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2831..2842
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2846..2849
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2850..2856
/evidence="ECO:0007829|PDB:2XWH"
TURN 2857..2859
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2861..2865
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2867..2878
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2885..2889
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2892..2896
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2898..2900
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2901..2909
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2911..2914
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2921..2934
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2939..2955
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2958..2967
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2969..2971
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2972..2974
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2982..2986
/evidence="ECO:0007829|PDB:2XWH"
TURN 2990..2993
/evidence="ECO:0007829|PDB:2XWH"
HELIX 2994..2996
/evidence="ECO:0007829|PDB:2XWH"
STRAND 2999..3001
/evidence="ECO:0007829|PDB:2XWH"
STRAND 3003..3005
/evidence="ECO:0007829|PDB:4ADP"
SEQUENCE 3033 AA; 329169 MW; F957F5C1A273BE9E CRC64;
MSTNPKPQRK TKRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRATR KTSERSQPRG
RRQPIPKDRR STGKSWGKPG YPWPLYGNEG LGWAGWLLSP RGSRPSWGPN DPRHRSRNVG
KVIDTLTCGF ADLMGYIPVV GAPLGGVARA LAHGVRVLED GVNFATGNLP GCSFSIFLLA
LLSCITTPVS AAEVKNISTG YMVTNDCTND SITWQLQAAV LHVPGCVPCE KVGNTSRCWI
PVSPNVAVQQ PGALTQGLRT HIDMVVMSAT LCSALYVGDL CGGVMLAAQM FIVSPQHHWF
VQDCNCSIYP GTITGHRMAW DMMMNWSPTA TMILAYAMRV PEVIIDIIGG AHWGVMFGLA
YFSMQGAWAK VVVILLLAAG VDAQTHTVGG STAHNARTLT GMFSLGARQK IQLINTNGSW
HINRTALNCN DSLHTGFLAS LFYTHSFNSS GCPERMSACR SIEAFRVGWG ALQYEDNVTN
PEDMRPYCWH YPPRQCGVVS ASSVCGPVYC FTPSPVVVGT TDRLGAPTYT WGENETDVFL
LNSTRPPQGS WFGCTWMNST GYTKTCGAPP CRIRADFNAS MDLLCPTDCF RKHPDTTYIK
CGSGPWLTPR CLIDYPYRLW HYPCTVNYTI FKIRMYVGGV EHRLTAACNF TRGDRCNLED
RDRSQLSPLL HSTTEWAILP CTYSDLPALS TGLLHLHQNI VDVQFMYGLS PALTKYIVRW
EWVVLLFLLL ADARVCACLW MLILLGQAEA ALEKLVVLHA ASAASCNGFL YFVIFFVAAW
YIKGRVVPLA TYSLTGLWSF GLLLLALPQQ AYAYDASVHG QIGAALLVLI TLFTLTPGYK
TLLSRFLWWL CYLLTLAEAM VQEWAPPMQV RGGRDGIIWA VAIFCPGVVF DITKWLLAVL
GPAYLLKGAL TRVPYFVRAH ALLRMCTMVR HLAGGRYVQM VLLALGRWTG TYIYDHLTPM
SDWAANGLRD LAVAVEPIIF SPMEKKVIVW GAETAACGDI LHGLPVSARL GREVLLGPAD
GYTSKGWSLL APITAYAQQT RGLLGTIVVS MTGRDKTEQA GEIQVLSTVT QSFLGTTISG
VLWTVYHGAG NKTLAGSRGP VTQMYSSAEG DLVGWPSPPG TKSLEPCTCG AVDLYLVTRN
ADVIPARRRG DKRGALLSPR PLSTLKGSSG GPVLCPRGHA VGVFRAAVCS RGVAKSIDFI
PVETLDIVTR SPTFSDNSTP PAVPQTYQVG YLHAPTGSGK STKVPVAYAA QGYKVLVLNP
SVAATLGFGA YLSKAHGINP NIRTGVRTVT TGAPITYSTY GKFLADGGCA GGAYDIIICD
ECHAVDSTTI LGIGTVLDQA ETAGVRLTVL ATATPPGSVT TPHPNIEEVA LGQEGEIPFY
GRAIPLSYIK GGRHLIFCHS KKKCDELAAA LRGMGLNAVA YYRGLDVSVI PTQGDVVVVA
TDALMTGFTG DFDSVIDCNV AVTQVVDFSL DPTFTITTQT VPQDAVSRSQ RRGRTGRGRL
GIYRYVSTGE RASGMFDSVV LCECYDAGAA WYELTPAETT VRLRAYFNTP GLPVCQDHLE
FWEAVFTGLT HIDAHFLSQT KQSGENFAYL TAYQATVCAR AKAPPPSWDV MWKCLTRLKP
TLVGPTPLLY RLGSVTNEVT LTHPVTKYIA TCMQADLEVM TSTWVLAGGV LAAVAAYCLA
TGCVCIIGRL HVNQRAVVAP DKEVLYEAFD EMEECASRAA LIEEGQRIAE MLKSKIQGLL
QQASKQAQDI QPAVQASWPK VEQFWAKHMW NFISGIQYLA GLSTLPGNPA VASMMAFSAA
LTSPLSTSTT ILLNILGGWL ASQIAPPAGA TGFVVSGLVG AAVGSIGLGK VLVDILAGYG
AGISGALVAF KIMSGEKPSM EDVVNLLPGI LSPGALVVGV ICAAILRRHV GPGEGAVQWM
NRLIAFASRG NHVAPTHYVT ESDASQRVTQ LLGSLTITSL LRRLHNWITE DCPIPCSGSW
LRDVWDWVCT ILTDFKNWLT SKLFPKMPGL PFISCQKGYK GVWAGTGIMT TRCPCGANIS
GNVRLGSMRI TGPKTCMNIW QGTFPINCYT EGQCVPKPAP NFKIAIWRVA ASEYAEVTQH
GSYHYITGLT TDNLKVPCQL PSPEFFSWVD GVQIHRFAPI PKPFFRDEVS FCVGLNSFVV
GSQLPCDPEP DTDVLTSMLT DPSHITAETA ARRLARGSPP SEASSSASQL SAPSLRATCT
THGKAYDVDM VDANLFMGGD VTRIESESKV VVLDSLDPMV EERSDLEPSI PSEYMLPKKR
FPPALPAWAR PDYNPPLVES WKRPDYQPAT VAGCALPPPK KTPTPPPRRR RTVGLSESSI
ADALQQLAIK SFGQPPPSGD SGLSTGADAA DSGSRTPPDE LALSETGSIS SMPPLEGEPG
DPDLEPEQVE LQPPPQGGVV TPGSGSGSWS TCSEEDDSVV CCSMSYSWTG ALITPCSPEE
EKLPINPLSN SLLRYHNKVY CTTSKSASLR AKKVTFDRMQ ALDAHYDSVL KDIKLAASKV
TARLLTLEEA CQLTPPHSAR SKYGFGAKEV RSLSGRAVNH IKSVWKDLLE DTQTPIPTTI
MAKNEVFCVD PTKGGKKAAR LIVYPDLGVR VCEKMALYDI TQKLPQAVMG ASYGFQYSPA
QRVEFLLKAW AEKKDPMGFS YDTRCFDSTV TERDIRTEES IYRACSLPEE AHTAIHSLTE
RLYVGGPMFN SKGQTCGYRR CRASGVLTTS MGNTITCYVK ALAACKAAGI IAPTMLVCGD
DLVVISESQG TEEDERNLRA FTEAMTRYSA PPGDPPRPEY DLELITSCSS NVSVALGPQG
RRRYYLTRDP TTPIARAAWE TVRHSPVNSW LGNIIQYAPT IWARMVLMTH FFSILMAQDT
LDQNLNFEMY GAVYSVSPLD LPAIIERLHG LDAFSLHTYT PHELTRVASA LRKLGAPPLR
AWKSRARAVR ASLISRGGRA AVCGRYLFNW AVKTKLKLTP LPEARLLDLS SWFTVGAGGG
DIYHSVSRAR PRLLLLGLLL LFVGVGLFLL PAR


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