POLN_SINDV
ID POLN_SINDV Reviewed; 2513 AA.
AC P03317; Q87644;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 10-APR-2019, sequence version 2.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Polyprotein P1234;
DE Short=P1234;
DE AltName: Full=Non-structural polyprotein;
DE AltName: Full=p270 nonstructural polyprotein;
DE Contains:
DE RecName: Full=Polyprotein P123';
DE Short=P123';
DE Contains:
DE RecName: Full=Polyprotein P123;
DE Short=P123;
DE Contains:
DE RecName: Full=mRNA-capping enzyme nsP1;
DE EC=2.1.1.- {ECO:0000250|UniProtKB:P27282};
DE EC=2.7.7.- {ECO:0000269|PubMed:7831320};
DE AltName: Full=Non-structural protein 1;
DE Contains:
DE RecName: Full=Protease nsP2;
DE EC=3.1.3.33 {ECO:0000250|UniProtKB:P08411};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q8JUX6};
DE EC=3.6.1.15 {ECO:0000250|UniProtKB:Q8JUX6};
DE EC=3.6.4.13 {ECO:0000250|UniProtKB:Q8JUX6};
DE AltName: Full=Non-structural protein 2;
DE Short=nsP2;
DE Contains:
DE RecName: Full=Non-structural protein 3';
DE Short=nsP3';
DE EC=3.1.3.84 {ECO:0000305};
DE Contains:
DE RecName: Full=Non-structural protein 3;
DE Short=nsP3;
DE EC=3.1.3.84 {ECO:0000250|UniProtKB:Q8JUX6};
DE Contains:
DE RecName: Full=RNA-directed RNA polymerase nsP4;
DE EC=2.7.7.19 {ECO:0000269|PubMed:17005674};
DE EC=2.7.7.48 {ECO:0000255|PROSITE-ProRule:PRU00539, ECO:0000269|PubMed:19036396};
DE AltName: Full=Non-structural protein 4;
DE Short=nsP4;
OS Sindbis virus (SINV).
OC Viruses; Riboviria; Orthornavirae; Kitrinoviricota; Alsuviricetes;
OC Martellivirales; Togaviridae; Alphavirus.
OX NCBI_TaxID=11034;
OH NCBI_TaxID=48156; Acrocephalus scirpaceus (Eurasian reed-warbler).
OH NCBI_TaxID=7158; Aedes.
OH NCBI_TaxID=53527; Culex.
OH NCBI_TaxID=9606; Homo sapiens (Human).
OH NCBI_TaxID=45807; Motacilla alba (White wagtail) (Pied wagtail).
OH NCBI_TaxID=177155; Streptopelia turtur.
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=6322438; DOI=10.1016/0042-6822(84)90428-8;
RA Strauss E.G., Rice C.M., Strauss J.H.;
RT "Complete nucleotide sequence of the genomic RNA of Sindbis virus.";
RL Virology 133:92-110(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 1-54.
RX PubMed=6308269; DOI=10.1016/s0022-2836(83)80319-2;
RA Ou J.H., Strauss E.G., Strauss J.H.;
RT "The 5'-terminal sequences of the genomic RNAs of several alphaviruses.";
RL J. Mol. Biol. 168:1-15(1983).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 1429-2512.
RX PubMed=6577423; DOI=10.1073/pnas.80.17.5271;
RA Strauss E.G., Rice C.M., Strauss J.H.;
RT "Sequence coding for the alphavirus nonstructural proteins is interrupted
RT by an opal termination codon.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:5271-5275(1983).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 2431-2512.
RX PubMed=6291034; DOI=10.1073/pnas.79.17.5235;
RA Ou J.-H., Rice C.M., Dalgarno L., Strauss E.G., Strauss J.H.;
RT "Sequence studies of several alphavirus genomic RNAs in the region
RT containing the start of the subgenomic RNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 79:5235-5239(1982).
RN [5]
RP SUBCELLULAR LOCATION (RNA-DIRECTED RNA POLYMERASE NSP4).
RX PubMed=2904446; DOI=10.1083/jcb.107.6.2075;
RA Froshauer S., Kartenbeck J., Helenius A.;
RT "Alphavirus RNA replicase is located on the cytoplasmic surface of
RT endosomes and lysosomes.";
RL J. Cell Biol. 107:2075-2086(1988).
RN [6]
RP PROTEOLYTIC CLEAVAGE (POLYPROTEIN P123).
RX PubMed=2529379; DOI=10.1128/jvi.63.11.4653-4664.1989;
RA Hardy W.R., Strauss J.H.;
RT "Processing the nonstructural polyproteins of sindbis virus: nonstructural
RT proteinase is in the C-terminal half of nsP2 and functions both in cis and
RT in trans.";
RL J. Virol. 63:4653-4664(1989).
RN [7]
RP PROTEOLYTIC CLEAVAGE (POLYPROTEIN P123), AND MUTAGENESIS OF GLY-539 AND
RP GLY-1346.
RX PubMed=2141206; DOI=10.1016/0042-6822(90)90459-5;
RA Shirako Y., Strauss J.H.;
RT "Cleavage between nsP1 and nsP2 initiates the processing pathway of Sindbis
RT virus nonstructural polyprotein P123.";
RL Virology 177:54-64(1990).
RN [8]
RP MUTAGENESIS OF TYR-1896, AND RIBOSOMAL READTHROUGH.
RX PubMed=2521676; DOI=10.1128/jvi.63.3.1326-1337.1989;
RA Li G.P., Rice C.M.;
RT "Mutagenesis of the in-frame opal termination codon preceding nsP4 of
RT Sindbis virus: studies of translational readthrough and its effect on virus
RT replication.";
RL J. Virol. 63:1326-1337(1989).
RN [9]
RP PROTEOLYTIC CLEAVAGE (POLYPROTEIN P1234), AND PROTEOLYTIC CLEAVAGE
RP (POLYPROTEIN P123).
RX PubMed=2142454;
RA de Groot R.J., Hardy W.R., Shirako Y., Strauss J.H.;
RT "Cleavage-site preferences of Sindbis virus polyproteins containing the
RT non-structural proteinase. Evidence for temporal regulation of polyprotein
RT processing in vivo.";
RL EMBO J. 9:2631-2638(1990).
RN [10]
RP UBIQUITINATION (RNA-DIRECTED RNA POLYMERASE NSP4).
RX PubMed=1924357; DOI=10.1073/pnas.88.20.8967;
RA de Groot R.J., Ruemenapf T., Kuhn R.J., Strauss E.G., Strauss J.H.;
RT "Sindbis virus RNA polymerase is degraded by the N-end rule pathway.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8967-8971(1991).
RN [11]
RP FUNCTION (MRNA-CAPPING ENZYME NSP1).
RX PubMed=1824787; DOI=10.1128/jvi.65.2.985-988.1991;
RA Wang Y.F., Sawicki S.G., Sawicki D.L.;
RT "Sindbis virus nsP1 functions in negative-strand RNA synthesis.";
RL J. Virol. 65:985-988(1991).
RN [12]
RP MUTAGENESIS OF CYS-1021; HIS-1098 AND TRP-1099.
RX PubMed=1448929; DOI=10.1016/0042-6822(92)90268-t;
RA Strauss E.G., De Groot R.J., Levinson R., Strauss J.H.;
RT "Identification of the active site residues in the nsP2 proteinase of
RT Sindbis virus.";
RL Virology 191:932-940(1992).
RN [13]
RP FUNCTION (RNA-DIRECTED RNA POLYMERASE NSP4), FUNCTION (POLYPROTEIN P123),
RP AND PROTEOLYTIC CLEAVAGE (POLYPROTEIN P1234).
RX PubMed=7517863; DOI=10.1002/j.1460-2075.1994.tb06587.x;
RA Lemm J.A., Ruemenapf T., Strauss E.G., Strauss J.H., Rice C.M.;
RT "Polypeptide requirements for assembly of functional Sindbis virus
RT replication complexes: a model for the temporal regulation of minus- and
RT plus-strand RNA synthesis.";
RL EMBO J. 13:2925-2934(1994).
RN [14]
RP FUNCTION (NON-STRUCTURAL PROTEIN 3).
RX PubMed=8057460; DOI=10.1128/jvi.68.9.5781-5791.1994;
RA LaStarza M.W., Lemm J.A., Rice C.M.;
RT "Genetic analysis of the nsP3 region of Sindbis virus: evidence for roles
RT in minus-strand and subgenomic RNA synthesis.";
RL J. Virol. 68:5781-5791(1994).
RN [15]
RP FUNCTION (RNA-DIRECTED RNA POLYMERASE NSP4), FUNCTION (POLYPROTEIN P123),
RP PROTEOLYTIC CLEAVAGE (POLYPROTEIN P123), AND PROTEOLYTIC CLEAVAGE
RP (POLYPROTEIN P1234).
RX PubMed=8107248; DOI=10.1128/jvi.68.3.1874-1885.1994;
RA Shirako Y., Strauss J.H.;
RT "Regulation of Sindbis virus RNA replication: uncleaved P123 and nsP4
RT function in minus-strand RNA synthesis, whereas cleaved products from P123
RT are required for efficient plus-strand RNA synthesis.";
RL J. Virol. 68:1874-1885(1994).
RN [16]
RP FUNCTION (MRNA-CAPPING ENZYME NSP1), AND CATALYTIC ACTIVITY (MRNA-CAPPING
RP ENZYME NSP1).
RX PubMed=7831320; DOI=10.1073/pnas.92.2.507;
RA Ahola T., Kaeaeriaeinen L.;
RT "Reaction in alphavirus mRNA capping: formation of a covalent complex of
RT nonstructural protein nsP1 with 7-methyl-GMP.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:507-511(1995).
RN [17]
RP FUNCTION (PROTEASE NSP2), AND MUTAGENESIS OF GLU-703; VAL-815 AND LEU-956.
RX PubMed=8627744; DOI=10.1128/jvi.70.5.2706-2719.1996;
RA De I., Sawicki S.G., Sawicki D.L.;
RT "Sindbis virus RNA-negative mutants that fail to convert from minus-strand
RT to plus-strand synthesis: role of the nsP2 protein.";
RL J. Virol. 70:2706-2719(1996).
RN [18]
RP MUTAGENESIS OF HIS-39; HIS-81; ASP-91; ARG-94; TYR-249 AND ILE-369.
RX PubMed=8610444; DOI=10.1006/viro.1996.0147;
RA Wang H.-L., O'Rear J., Stollar V.;
RT "Mutagenesis of the Sindbis virus nsP1 protein: effects on
RT methyltransferase activity and viral infectivity.";
RL Virology 217:527-531(1996).
RN [19]
RP MUTAGENESIS OF TYR-1904.
RX PubMed=9499091; DOI=10.1128/jvi.72.3.2310-2315.1998;
RA Shirako Y., Strauss J.H.;
RT "Requirement for an aromatic amino acid or histidine at the N-terminus of
RT Sindbis virus RNA polymerase.";
RL J. Virol. 72:2310-2315(1998).
RN [20]
RP PALMITOYLATION AT CYS-420, AND MUTAGENESIS OF CYS-420.
RX PubMed=10888610; DOI=10.1128/jvi.74.15.6725-6733.2000;
RA Ahola T., Kujala P., Tuittila M., Blom T., Laakkonen P., Hinkkanen A.,
RA Auvinen P.;
RT "Effects of palmitoylation of replicase protein nsP1 on alphavirus
RT infection.";
RL J. Virol. 74:6725-6733(2000).
RN [21]
RP TRANSLATION SHUTOFF.
RX PubMed=16391235; DOI=10.1101/gad.357006;
RA Ventoso I., Sanz M.A., Molina S., Berlanga J.J., Carrasco L., Esteban M.;
RT "Translational resistance of late alphavirus mRNA to eIF2alpha
RT phosphorylation: a strategy to overcome the antiviral effect of protein
RT kinase PKR.";
RL Genes Dev. 20:87-100(2006).
RN [22]
RP SUBCELLULAR LOCATION (NON-STRUCTURAL PROTEIN 3).
RX PubMed=16571828; DOI=10.1128/jvi.80.8.4122-4134.2006;
RA Frolova E., Gorchakov R., Garmashova N., Atasheva S., Vergara L.A.,
RA Frolov I.;
RT "Formation of nsP3-specific protein complexes during Sindbis virus
RT replication.";
RL J. Virol. 80:4122-4134(2006).
RN [23]
RP FUNCTION (RNA-DIRECTED RNA POLYMERASE NSP4), COFACTOR (RNA-DIRECTED RNA
RP POLYMERASE NSP4), BIOPHYSICOCHEMICAL PROPERTIES (RNA-DIRECTED RNA
RP POLYMERASE NSP4), AND CATALYTIC ACTIVITY (RNA-DIRECTED RNA POLYMERASE
RP NSP4).
RX PubMed=17005674; DOI=10.1128/jvi.01067-06;
RA Tomar S., Hardy R.W., Smith J.L., Kuhn R.J.;
RT "Catalytic core of alphavirus nonstructural protein nsP4 possesses terminal
RT adenylyltransferase activity.";
RL J. Virol. 80:9962-9969(2006).
RN [24]
RP FUNCTION (PROTEASE NSP2).
RX PubMed=17108023; DOI=10.1128/jvi.02073-06;
RA Garmashova N., Gorchakov R., Volkova E., Paessler S., Frolova E.,
RA Frolov I.;
RT "The Old World and New World alphaviruses use different virus-specific
RT proteins for induction of transcriptional shutoff.";
RL J. Virol. 81:2472-2484(2007).
RN [25]
RP FUNCTION (NON-STRUCTURAL PROTEIN 3), INTERACTION WITH HOST G3BP1
RP (NON-STRUCTURAL PROTEIN 3), AND INTERACTION WITH HOST G3BP2 (NON-STRUCTURAL
RP PROTEIN 3).
RX PubMed=18684830; DOI=10.1128/jvi.01011-08;
RA Gorchakov R., Garmashova N., Frolova E., Frolov I.;
RT "Different types of nsP3-containing protein complexes in Sindbis virus-
RT infected cells.";
RL J. Virol. 82:10088-10101(2008).
RN [26]
RP FUNCTION (RNA-DIRECTED RNA POLYMERASE NSP4), BIOPHYSICOCHEMICAL PROPERTIES
RP (RNA-DIRECTED RNA POLYMERASE NSP4), CATALYTIC ACTIVITY (RNA-DIRECTED RNA
RP POLYMERASE NSP4), MUTAGENESIS OF 2367-GLU-GLU-2368, AND COFACTOR
RP (RNA-DIRECTED RNA POLYMERASE NSP4).
RX PubMed=19036396; DOI=10.1016/j.virol.2008.10.030;
RA Rubach J.K., Wasik B.R., Rupp J.C., Kuhn R.J., Hardy R.W., Smith J.L.;
RT "Characterization of purified Sindbis virus nsP4 RNA-dependent RNA
RT polymerase activity in vitro.";
RL Virology 384:201-208(2009).
RN [27]
RP FUNCTION (PROTEASE NSP2), AND MUTAGENESIS OF PRO-1266.
RX PubMed=22514352; DOI=10.1128/jvi.00541-12;
RA Akhrymuk I., Kulemzin S.V., Frolova E.I.;
RT "Evasion of the innate immune response: the Old World alphavirus nsP2
RT protein induces rapid degradation of Rpb1, a catalytic subunit of RNA
RT polymerase II.";
RL J. Virol. 86:7180-7191(2012).
RN [28]
RP FUNCTION (NON-STRUCTURAL PROTEIN 3), DOMAIN (NON-STRUCTURAL PROTEIN 3), AND
RP CATALYTIC ACTIVITY (NON-STRUCTURAL PROTEIN 3).
RX PubMed=28150709; DOI=10.1038/srep41746;
RA Eckei L., Krieg S., Buetepage M., Lehmann A., Gross A., Lippok B.,
RA Grimm A.R., Kuemmerer B.M., Rossetti G., Luescher B., Verheugd P.;
RT "The conserved macrodomains of the non-structural proteins of Chikungunya
RT virus and other pathogenic positive strand RNA viruses function as mono-
RT ADP-ribosylhydrolases.";
RL Sci. Rep. 7:41746-41746(2017).
RN [29]
RP REVIEW.
RX PubMed=29419763; DOI=10.3390/v10020070;
RA Carrasco L., Sanz M.A., Gonzalez-Almela E.;
RT "The regulation of translation in alphavirus-infected cells.";
RL Viruses 10:0-0(2018).
RN [30]
RP FUNCTION (PROTEASE NSP2), AND MUTAGENESIS OF CYS-1040; PRO-1223; GLN-1224
RP AND PRO-1266.
RX PubMed=30232189; DOI=10.1128/jvi.01388-18;
RA Akhrymuk I., Frolov I., Frolova E.I.;
RT "Sindbis virus infection causes cell death by nsP2-induced transcriptional
RT shutoff or by nsP3-dependent translational shutoff.";
RL J. Virol. 92:0-0(2018).
RN [31] {ECO:0007744|PDB:4GUA}
RP X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 1011-1675 IN COMPLEX WITH ZINC,
RP DOMAIN (NON-STRUCTURAL PROTEIN 3), AND MUTAGENESIS OF CYS-1610; CYS-1612;
RP CYS-1635 AND CYS-1653.
RX PubMed=23010928; DOI=10.1073/pnas.1210418109;
RA Shin G., Yost S.A., Miller M.T., Elrod E.J., Grakoui A., Marcotrigiano J.;
RT "Structural and functional insights into alphavirus polyprotein processing
RT and pathogenesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:16534-16539(2012).
CC -!- FUNCTION: [Polyprotein P1234]: Inactive precursor of the viral
CC replicase, which is activated by cleavages carried out by the viral
CC protease nsP2. {ECO:0000250|UniProtKB:Q8JUX6}.
CC -!- FUNCTION: [Polyprotein P123]: The early replication complex formed by
CC the polyprotein P123 and nsP4 synthesizes minus-strand RNAs
CC (PubMed:8107248, PubMed:7517863). Polyprotein P123 is a short-lived
CC polyprotein that accumulates during early stage of infection
CC (PubMed:8107248, PubMed:7517863). As soon P123 is cleaved into mature
CC proteins, the plus-strand RNAs synthesis begins (PubMed:8107248,
CC PubMed:7517863). {ECO:0000269|PubMed:7517863,
CC ECO:0000269|PubMed:8107248}.
CC -!- FUNCTION: [Polyprotein P123']: The early replication complex formed by
CC the polyprotein P123' and nsP4 synthesizes minus-strand RNAs
CC (Probable). Polyprotein P123' is a short-lived polyprotein that
CC accumulates during early stage of infection (Probable). As soon P123'
CC is cleaved into mature proteins, the plus-strand RNAs synthesis begins
CC (Probable). {ECO:0000305|PubMed:7517863, ECO:0000305|PubMed:8107248}.
CC -!- FUNCTION: [mRNA-capping enzyme nsP1]: Cytoplasmic capping enzyme that
CC catalyzes two virus-specific reactions: methyltransferase and nsP1
CC guanylyltransferase (PubMed:7831320). mRNA-capping is necessary since
CC all viral RNAs are synthesized in the cytoplasm, and host capping
CC enzymes are restricted to the nucleus (Probable). The enzymatic
CC reaction involves a covalent link between 7-methyl-GMP and nsP1,
CC whereas eukaryotic capping enzymes form a covalent complex only with
CC GMP (Probable). nsP1 capping consists in the following reactions: GTP
CC is first methylated into 7-methyl-GMP and then is covalently linked to
CC nsP1 to form the m7GMp-nsP1 complex from which 7-methyl-GMP complex is
CC transferred to the mRNA to create the cap structure (Probable). NsP1 is
CC needed for the initiation of the minus-strand RNAs synthesis
CC (PubMed:1824787). Probably serves as a membrane anchor for the
CC replication complex composed of nsP1-nsP4 (By similarity).
CC Palmitoylated nsP1 is remodeling host cell cytoskeleton, and induces
CC filopodium-like structure formation at the surface of the host cell (By
CC similarity). {ECO:0000250|UniProtKB:P08411,
CC ECO:0000250|UniProtKB:Q8JUX6, ECO:0000269|PubMed:1824787,
CC ECO:0000269|PubMed:7831320, ECO:0000305, ECO:0000305|PubMed:7831320}.
CC -!- FUNCTION: [Protease nsP2]: Multifunctional protein whose N-terminus is
CC part of the RNA polymerase complex and displays NTPase, RNA
CC triphosphatase and helicase activities (By similarity). NTPase and RNA
CC triphosphatase are involved in viral RNA capping and helicase keeps a
CC check on the dsRNA replication intermediates (By similarity). The C-
CC terminus harbors a protease that specifically cleaves the polyproteins
CC and releases the mature proteins (By similarity). Required for the
CC shutoff of minus-strand RNAs synthesis (PubMed:8627744). Specifically
CC inhibits the host IFN response by promoting the nuclear export of host
CC STAT1 (By similarity). Also inhibits host transcription by inducing
CC rapid proteasome-dependent degradation of POLR2A, a catalytic subunit
CC of the RNAPII complex (PubMed:22514352, PubMed:17108023,
CC PubMed:30232189). The resulting inhibition of cellular protein
CC synthesis serves to ensure maximal viral gene expression and to evade
CC host immune response (Probable). {ECO:0000250|UniProtKB:P08411,
CC ECO:0000250|UniProtKB:Q8JUX6, ECO:0000269|PubMed:17108023,
CC ECO:0000269|PubMed:22514352, ECO:0000269|PubMed:30232189,
CC ECO:0000269|PubMed:8627744, ECO:0000305|PubMed:22514352}.
CC -!- FUNCTION: [Non-structural protein 3]: Seems to be essential for minus-
CC strand RNAs and subgenomic 26S mRNAs synthesis (PubMed:8057460).
CC Displays mono-ADP-ribosylhydrolase activity (PubMed:28150709). ADP-
CC ribosylation is a post-translantional modification that controls
CC various processes of the host cell and the virus probably needs to
CC revert it for optimal viral replication (PubMed:28150709). Binds
CC proteins of G3BP family and sequesters them into the viral RNA
CC replication complexes thereby inhibiting the formation of host stress
CC granules on viral mRNAs (PubMed:18684830). The nsp3-G3BP complexes bind
CC viral RNAs and probably orchestrate the assembly of viral replication
CC complexes, thanks to the ability of G3BP family members to self-
CC assemble and bind DNA (By similarity). {ECO:0000250|UniProtKB:Q8JUX6,
CC ECO:0000269|PubMed:18684830, ECO:0000269|PubMed:28150709,
CC ECO:0000269|PubMed:8057460}.
CC -!- FUNCTION: [Non-structural protein 3']: Seems to be essential for minus-
CC strand RNAs and subgenomic 26S mRNAs synthesis (Probable). Displays
CC mono-ADP-ribosylhydrolase activity (Probable). ADP-ribosylation is a
CC post-translational modification that controls various processes of the
CC host cell and the virus probably needs to revert it for optimal viral
CC replication (Probable). Binds proteins of G3BP family and sequesters
CC them into the viral RNA replication complexes thereby inhibiting the
CC formation of host stress granules on viral mRNAs (Probable). The nsp3'-
CC G3BP complexes bind viral RNAs and probably orchestrate the assembly of
CC viral replication complexes, thanks to the ability of G3BP family
CC members to self-assemble and bind DNA (By similarity).
CC {ECO:0000250|UniProtKB:Q8JUX6, ECO:0000305|PubMed:18684830,
CC ECO:0000305|PubMed:28150709, ECO:0000305|PubMed:8057460}.
CC -!- FUNCTION: [RNA-directed RNA polymerase nsP4]: RNA dependent RNA
CC polymerase (PubMed:8107248, PubMed:7517863, PubMed:19036396).
CC Replicates genomic and antigenomic RNA by recognizing replications
CC specific signals. The early replication complex formed by the
CC polyprotein P123 and nsP4 synthesizes minus-strand RNAs
CC (PubMed:8107248, PubMed:7517863, PubMed:2529379). The late replication
CC complex composed of fully processed nsP1-nsP4 is responsible for the
CC production of genomic and subgenomic plus-strand RNAs (PubMed:8107248,
CC PubMed:7517863). The core catalytic domain of nsP4 also possesses
CC terminal adenylyltransferase (TATase) activity that is probably
CC involved in maintenance and repair of the poly(A) tail, an element
CC required for replication of the viral genome (PubMed:17005674).
CC {ECO:0000269|PubMed:17005674, ECO:0000269|PubMed:19036396,
CC ECO:0000269|PubMed:2529379, ECO:0000269|PubMed:7517863,
CC ECO:0000269|PubMed:8107248}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP + S-adenosyl-L-methionine = N(7)-methyl-GTP + S-adenosyl-
CC L-homocysteine; Xref=Rhea:RHEA:46948, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:87133;
CC Evidence={ECO:0000250|UniProtKB:P27282};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[nsP1 protein]-L-histidine + N(7)-methyl-GTP = [nsP1 protein]-
CC N(tele)-(N(7)-methylguanosine 5'-phospho)-L-histidine + diphosphate;
CC Xref=Rhea:RHEA:54792, Rhea:RHEA-COMP:13994, Rhea:RHEA-COMP:13995,
CC ChEBI:CHEBI:29979, ChEBI:CHEBI:33019, ChEBI:CHEBI:87133,
CC ChEBI:CHEBI:138334; Evidence={ECO:0000269|PubMed:7831320};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54793;
CC Evidence={ECO:0000269|PubMed:7831320};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[nsP1 protein]-N(tele)-(N(7)-methylguanosine 5'-phospho)-L-
CC histidine + a 5'-end diphospho-(purine-ribonucleoside) in mRNA + H(+)
CC = [nsP1 protein]-L-histidine + a 5'-end (N(7)-methyl 5'-
CC triphosphoguanosine)-(purine-ribonucleoside) in mRNA;
CC Xref=Rhea:RHEA:54800, Rhea:RHEA-COMP:12925, Rhea:RHEA-COMP:13929,
CC Rhea:RHEA-COMP:13994, Rhea:RHEA-COMP:13995, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29979, ChEBI:CHEBI:133968, ChEBI:CHEBI:138276,
CC ChEBI:CHEBI:138334; Evidence={ECO:0000250|UniProtKB:P27282};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 5'-end triphospho-(purine-ribonucleoside) in mRNA + H2O = a
CC 5'-end diphospho-(purine-ribonucleoside) in mRNA + H(+) + phosphate;
CC Xref=Rhea:RHEA:11008, Rhea:RHEA-COMP:13929, Rhea:RHEA-COMP:13942,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:138276, ChEBI:CHEBI:138288; EC=3.1.3.33;
CC Evidence={ECO:0000250|UniProtKB:P08411};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-
CC diphosphate + H(+) + phosphate; Xref=Rhea:RHEA:23680,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57930, ChEBI:CHEBI:61557; EC=3.6.1.15;
CC Evidence={ECO:0000250|UniProtKB:Q8JUX6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13;
CC Evidence={ECO:0000250|UniProtKB:Q8JUX6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA-
CC COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395;
CC EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539,
CC ECO:0000269|PubMed:19036396};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + RNA(n) = diphosphate + RNA(n)-3'-adenine ribonucleotide;
CC Xref=Rhea:RHEA:11332, Rhea:RHEA-COMP:14527, Rhea:RHEA-COMP:17347,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:140395,
CC ChEBI:CHEBI:173115; EC=2.7.7.19;
CC Evidence={ECO:0000269|PubMed:17005674};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4-O-(ADP-D-ribosyl)-L-aspartyl-[protein] + H2O = ADP-D-ribose
CC + H(+) + L-aspartyl-[protein]; Xref=Rhea:RHEA:54428, Rhea:RHEA-
CC COMP:9867, Rhea:RHEA-COMP:13832, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29961, ChEBI:CHEBI:57967,
CC ChEBI:CHEBI:138102; Evidence={ECO:0000269|PubMed:28150709};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54429;
CC Evidence={ECO:0000269|PubMed:28150709};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + H2O = ADP-D-ribose
CC + H(+) + L-glutamyl-[protein]; Xref=Rhea:RHEA:58248, Rhea:RHEA-
CC COMP:10208, Rhea:RHEA-COMP:15089, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29973, ChEBI:CHEBI:57967,
CC ChEBI:CHEBI:142540; Evidence={ECO:0000269|PubMed:28150709};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58249;
CC Evidence={ECO:0000269|PubMed:28150709};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ADP-beta-D-ribose 1''-phosphate + H2O = ADP-D-ribose +
CC phosphate; Xref=Rhea:RHEA:25029, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:57967, ChEBI:CHEBI:58753; EC=3.1.3.84;
CC Evidence={ECO:0000250|UniProtKB:Q8JUX6};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25030;
CC Evidence={ECO:0000250|UniProtKB:Q8JUX6};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:17005674};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:17005674};
CC Note=For nsP4 adenylyltransferase activity; Mn(2+) supports catalysis
CC at 60% of the levels observed with Mg(2+).
CC {ECO:0000269|PubMed:17005674};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:19036396};
CC Note=For nsP4 RNA-directed RNA polymerase activity.
CC {ECO:0000269|PubMed:19036396};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P27282};
CC Note=For nsP1 guanylylation. {ECO:0000250|UniProtKB:P27282};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Note=For nsP2 RNA triphosphatase activity.
CC {ECO:0000250|UniProtKB:Q8JUX6};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Note=For nsP2 NTPase activity. {ECO:0000250|UniProtKB:Q8JUX6};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 8.0-8.5 for nsP4 polymerase and adenylyltransferase
CC activities. {ECO:0000269|PubMed:17005674,
CC ECO:0000269|PubMed:19036396};
CC Temperature dependence:
CC Optimum temperature is 25 degrees Celsius for nsP4
CC adenylyltransferase activity. {ECO:0000269|PubMed:17005674};
CC -!- SUBUNIT: [mRNA-capping enzyme nsP1]: Interacts with non-structural
CC protein 3 (By similarity). Interacts with RNA-directed RNA polymerase
CC nsP4 (By similarity). Interacts with protease nsP2 (By similarity).
CC interacts with itself (By similarity). {ECO:0000250|UniProtKB:P27282}.
CC -!- SUBUNIT: [Non-structural protein 3]: Interacts with mRNA-capping enzyme
CC nsP1 (By similarity). Interacts with host DDX1 (By similarity).
CC Interacts with host DDX3 (By similarity). Interacts (via C-terminus)
CC with host G3BP1; this interaction inhibits the formation of host stress
CC granules on viral mRNAs and the nsp3-G3BP1 complexes bind viral RNAs
CC and probably orchestrate the assembly of viral replication complexes
CC (PubMed:18684830). Interacts (via C-terminus) with host G3BP2; this
CC interaction inhibits the formation of host stress granules on viral
CC mRNAs and the nsp3-G3BP2 complexes bind viral RNAs and probably
CC orchestrate the assembly of viral replication complexes
CC (PubMed:18684830). {ECO:0000250|UniProtKB:P27282,
CC ECO:0000269|PubMed:18684830}.
CC -!- SUBUNIT: [RNA-directed RNA polymerase nsP4]: Interacts with mRNA-
CC capping enzyme nsP1 (By similarity). Interacts with protease nsP2 (By
CC similarity). interacts with itself (By similarity).
CC {ECO:0000250|UniProtKB:P27282}.
CC -!- SUBUNIT: [Protease nsP2]: Interacts with RNA-directed RNA polymerase
CC nsP4 (By similarity). Interacts with mRNA-capping enzyme nsP1 (By
CC similarity). Interacts with KPNA1/karyopherin-alpha1; this interaction
CC probably allows the active transport of protease nsP2 into the host
CC nucleus (By similarity). {ECO:0000250|UniProtKB:P27282}.
CC -!- SUBCELLULAR LOCATION: [Polyprotein P1234]: Host cytoplasmic vesicle
CC membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}.
CC Note=Part of cytoplasmic vesicles, which are probably formed at the
CC plasma membrane and internalized leading to late endosomal/lysosomal
CC spherules containing the replication complex. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: [Polyprotein P123']: Host cytoplasmic vesicle
CC membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}.
CC Note=Part of cytoplasmic vesicles, which are probably formed at the
CC plasma membrane and internalized leading to late endosomal/lysosomal
CC spherules containing the replication complex. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: [Polyprotein P123]: Host cytoplasmic vesicle
CC membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}.
CC Note=Part of cytoplasmic vesicles, which are probably formed at the
CC plasma membrane and internalized leading to late endosomal/lysosomal
CC spherules containing the replication complex. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: [mRNA-capping enzyme nsP1]: Host cytoplasmic
CC vesicle membrane {ECO:0000250|UniProtKB:P08411}; Lipid-anchor
CC {ECO:0000250|UniProtKB:P08411}. Host cell membrane
CC {ECO:0000250|UniProtKB:P08411}; Lipid-anchor
CC {ECO:0000250|UniProtKB:P08411}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:P08411}. Host cell projection, host filopodium
CC {ECO:0000250|UniProtKB:P08411}. Note=In the late phase of infection,
CC the polyprotein is quickly cleaved before localization to cellular
CC membranes. Then a fraction of nsP1 localizes to the inner surface of
CC the plasma membrane and its filopodial extensions. Only the
CC palmitoylated nsP1 localizes to the host filopodia (By similarity).
CC NsP1 is also part of cytoplasmic vesicles, which are probably formed at
CC the plasma membrane and internalized leading to late
CC endosomal/lysosomal spherules containing the replication complex (By
CC similarity). {ECO:0000250|UniProtKB:P08411}.
CC -!- SUBCELLULAR LOCATION: [Protease nsP2]: Host cytoplasmic vesicle
CC membrane {ECO:0000250|UniProtKB:P08411}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P08411}. Host nucleus
CC {ECO:0000250|UniProtKB:P27282}. Host cytoplasm
CC {ECO:0000250|UniProtKB:P27282}. Note=In the late phase of infection,
CC the polyprotein is quickly cleaved before localization to cellular
CC membranes. Then approximately half of nsP2 is found in the nucleus (By
CC similarity). Shuttles between cytoplasm and nucleus (By similarity).
CC NsP2 is also part of cytoplasmic vesicles, which are probably formed at
CC the plasma membrane and internalized leading to late
CC endosomal/lysosomal spherules containing the replication complex (By
CC similarity). {ECO:0000250|UniProtKB:P08411,
CC ECO:0000250|UniProtKB:P27282}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 3]: Host cytoplasmic
CC vesicle membrane {ECO:0000269|PubMed:16571828}; Peripheral membrane
CC protein {ECO:0000305}. Note=In the late phase of infection, the
CC polyprotein is quickly cleaved before localization to cellular
CC membranes. Then nsP3 and nsP3' form aggregates in cytoplasm
CC (PubMed:16571828). NsP3 is also part of cytoplasmic vesicles, which are
CC probably formed at the plasma membrane and internalized leading to late
CC endosomal/lysosomal spherules containing the replication complex
CC (PubMed:16571828). {ECO:0000269|PubMed:16571828}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 3']: Host cytoplasmic
CC vesicle membrane {ECO:0000305|PubMed:16571828}; Peripheral membrane
CC protein {ECO:0000305}. Note=In the late phase of infection, the
CC polyprotein is quickly cleaved before localization to cellular
CC membranes. Then nsP3 and nsP3' form aggregates in cytoplasm (Probable).
CC NsP3' is also part of cytoplasmic vesicles, which are probably formed
CC at the plasma membrane and internalized leading to late
CC endosomal/lysosomal spherules containing the replication complex
CC (Probable). {ECO:0000305|PubMed:16571828}.
CC -!- SUBCELLULAR LOCATION: [RNA-directed RNA polymerase nsP4]: Host
CC cytoplasmic vesicle membrane; Peripheral membrane protein
CC {ECO:0000305|PubMed:2904446}. Note=NsP4 is part of cytoplasmic
CC vesicles, which are probably formed at the plasma membrane and
CC internalized leading to late endosomal/lysosomal spherules containing
CC the replication complex. {ECO:0000250|UniProtKB:P08411}.
CC -!- DOMAIN: [Protease nsP2]: The N-terminus exhibits NTPase and RNA
CC triphosphatase activities and is proposed to have helicase activity,
CC whereas the C-terminus possesses protease activity (By similarity).
CC Contains a nuclear localization signal and a nuclear export signal,
CC these two motifs are probably involved in the shuttling between the
CC cytoplasm and the nucleus of nsP2 (By similarity). The C-terminus is
CC required for promoting the export of host STAT1 (By similarity).
CC {ECO:0000250|UniProtKB:P27282, ECO:0000250|UniProtKB:Q8JUX6}.
CC -!- DOMAIN: [Non-structural protein 3]: In the N-terminus, the macro domain
CC displays a mono-ADP-ribosylhydrolase activity (PubMed:28150709). The
CC central part has a zinc-binding function (PubMed:23010928). The C-
CC terminus contains two FGDF motifs necessary and sufficient for
CC formation of the nsP3/G3BP1 complex (By similarity).
CC {ECO:0000250|UniProtKB:P08411, ECO:0000269|PubMed:23010928,
CC ECO:0000269|PubMed:28150709}.
CC -!- DOMAIN: [Non-structural protein 3']: In the N-terminus, the macro
CC domain displays a mono-ADP-ribosylhydrolase activity (Probable). The
CC central part has a zinc-binding function (Probable). The C-terminus
CC contains two FGDF motifs necessary and sufficient for formation of the
CC nsP3'/G3BP1 complex (By similarity). {ECO:0000250|UniProtKB:P08411,
CC ECO:0000305|PubMed:23010928, ECO:0000305|PubMed:28150709}.
CC -!- PTM: [Polyprotein P1234]: Specific enzymatic cleavages in vivo yield
CC mature proteins (PubMed:2142454, PubMed:8107248). The processing of the
CC polyprotein is temporally regulated (PubMed:2142454). In early stages
CC (1.7 hpi), P1234 is first cleaved in trans through its nsP2 protease
CC activity, releasing P123' and nsP4, which associate to form the early
CC replication complex (PubMed:2142454, PubMed:8107248) (Probable). At the
CC same time, P1234 is also cut at the nsP1/nsP2 site early in infection
CC but with lower efficiency (PubMed:2142454). After replication of the
CC viral minus-strand RNAs (4 hpi), the polyproteins are cut at the
CC nsP1/nsP2 and nsP2/nsP3 sites very efficiently, preventing accumulation
CC of P123' and P1234 and allowing the formation of the late replication
CC complex (PubMed:2142454, PubMed:8107248) (Probable). NsP3'/nsP4 site is
CC not cleaved anymore and P34 is produced rather than nsP4
CC (PubMed:2142454). {ECO:0000269|PubMed:2142454,
CC ECO:0000269|PubMed:8107248, ECO:0000305|PubMed:7517863}.
CC -!- PTM: [Polyprotein P123]: Specific enzymatic cleavages in vivo yield
CC mature proteins (PubMed:2142454, PubMed:2529379, PubMed:2141206,
CC PubMed:8107248). The processing of the polyprotein is temporally
CC regulated (PubMed:2142454). In early stages (1.7 hpi), P123 is cleaved
CC at the nsP1/nsP2 site with low efficiency (PubMed:2142454). After
CC replication of the viral minus-strand RNAs (4 hpi), the polyproteins
CC are cut at the nsP1/nsP2 and nsP2/nsP3 sites very efficiently,
CC preventing accumulation of P123 and allowing the formation of the late
CC replication complex (PubMed:2142454). {ECO:0000269|PubMed:2141206,
CC ECO:0000269|PubMed:2142454, ECO:0000269|PubMed:2529379,
CC ECO:0000269|PubMed:8107248}.
CC -!- PTM: [Polyprotein P123']: Specific enzymatic cleavages in vivo yield
CC mature proteins (Probable). The processing of the polyprotein is
CC temporally regulated (Probable). In early stages (1.7 hpi), P123' is
CC cleaved at the nsP1/nsP2 site with low efficiency (Probable). After
CC replication of the viral minus-strand RNAs (4 hpi), the polyproteins
CC are cut at the nsP1/nsP2 and nsP2/nsP3 sites very efficiently,
CC preventing accumulation of P123' and allowing the formation of the late
CC replication complex (Probable). {ECO:0000305|PubMed:2141206,
CC ECO:0000305|PubMed:2142454, ECO:0000305|PubMed:2529379,
CC ECO:0000305|PubMed:7517863, ECO:0000305|PubMed:8107248}.
CC -!- PTM: [mRNA-capping enzyme nsP1]: Palmitoylated by host
CC palmitoyltransferases ZDHHC2 and ZDHHC19.
CC {ECO:0000250|UniProtKB:Q8JUX6}.
CC -!- PTM: [Non-structural protein 3]: Phosphorylated by host on serines and
CC threonines. {ECO:0000250|UniProtKB:P08411}.
CC -!- PTM: [Non-structural protein 3']: Phosphorylated by host on serines and
CC threonines. {ECO:0000250|UniProtKB:P08411}.
CC -!- PTM: [RNA-directed RNA polymerase nsP4]: Ubiquitinated; targets the
CC protein for rapid degradation via the ubiquitin system
CC (PubMed:1924357). Nsp4 is present in extremely low quantities due to
CC low frequency of translation through the amber stop-codon and the
CC degradation by the ubiquitin pathway (PubMed:1924357).
CC {ECO:0000269|PubMed:1924357}.
CC -!- MISCELLANEOUS: Viral replication produces dsRNA in the late phase of
CC infection, resulting in a strong activation of host EIF2AK2/PKR,
CC leading to almost complete phosphorylation of EIF2A (PubMed:16391235).
CC This inactivates completely cellular translation initiation, resulting
CC shutoff of host proteins synthesis (PubMed:16391235). However,
CC phosphorylation of EIF2A is probably not the only mechanism responsible
CC for the host translation shutoff (PubMed:29419763). The viral
CC translation can still occur normally because it relies on a hairpin
CC structure in the coding region of sgRNA and is EIF2A-, EIF2D-,
CC EIF4G- EIF4A-independent (PubMed:29419763).
CC {ECO:0000269|PubMed:16391235, ECO:0000303|PubMed:29419763}.
CC -!- MISCELLANEOUS: The genome codes for P123, but readthrough of a
CC terminator codon UGA occurs between the codons for Tyr-1896 and Leu-
CC 1898 giving rise to P1234 (PubMed:2521676). P1234 is cleaved quickly by
CC nsP2 into P123' and nsP4 (By similarity). Further processing of p123'
CC gives nsP1, nsP2 and nsP3' which is 6 amino acids longer than nsP3
CC since the cleavage site is after the readthrough (By similarity). This
CC unusual molecular mechanism ensures that few nsP4 are produced compared
CC to other non-structural proteins (By similarity). Mutant viruses with
CC no alternative termination site grow significantly slower than wild-
CC type virus (PubMed:2521676). The opal termination codon is frequently
CC mutated to a sense codon on passage in cell culture (By similarity).
CC The presence of the opal codon may be a requirement for viral
CC maintenance in both vertebrate and invertebrate hosts and a selective
CC advantage may be conferred in cell culture for the sense codon (By
CC similarity). {ECO:0000250|UniProtKB:O90368,
CC ECO:0000269|PubMed:2521676}.
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DR EMBL; J02363; AAA96974.1; -; Genomic_RNA.
DR EMBL; J02363; AAA96975.1; ALT_SEQ; Genomic_RNA.
DR PIR; A03917; MNWVS.
DR RefSeq; NP_062888.1; NC_001547.1.
DR RefSeq; NP_062889.1; NC_001547.1.
DR PDB; 4GUA; X-ray; 2.85 A; A/B/C=1011-1675.
DR PDB; 7VB4; X-ray; 1.86 A; A/B=1994-2513.
DR PDB; 7VW5; X-ray; 2.30 A; A/B=1994-2513.
DR PDBsum; 4GUA; -.
DR PDBsum; 7VB4; -.
DR PDBsum; 7VW5; -.
DR SMR; P03317; -.
DR ELM; P03317; -.
DR MEROPS; C09.001; -.
DR SwissPalm; P03317; -.
DR PRIDE; P03317; -.
DR GeneID; 1502153; -.
DR GeneID; 1502154; -.
DR KEGG; vg:1502153; -.
DR KEGG; vg:1502154; -.
DR BRENDA; 3.4.22.B79; 5737.
DR BRENDA; 3.6.1.74; 5737.
DR Proteomes; UP000006710; Genome.
DR GO; GO:0044162; C:host cell cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0044176; C:host cell filopodium; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0070566; F:adenylyltransferase activity; IDA:UniProtKB.
DR GO; GO:0047407; F:ADP-ribosyl-[dinitrogen reductase] hydrolase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATP hydrolysis activity; IEA:RHEA.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008174; F:mRNA methyltransferase activity; IMP:CACAO.
DR GO; GO:0004651; F:polynucleotide 5'-phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0004652; F:polynucleotide adenylyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0003724; F:RNA helicase activity; IEA:UniProtKB-EC.
DR GO; GO:0003968; F:RNA-directed 5'-3' RNA polymerase activity; IDA:UniProtKB.
DR GO; GO:0006370; P:7-methylguanosine mRNA capping; IDA:UniProtKB.
DR GO; GO:0062030; P:negative regulation of stress granule assembly; IDA:UniProtKB.
DR GO; GO:0039690; P:positive stranded viral RNA replication; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0039563; P:suppression by virus of host JAK-STAT cascade via inhibition of STAT1 activity; IEA:UniProtKB-KW.
DR GO; GO:0039523; P:suppression by virus of host mRNA transcription via inhibition of RNA polymerase II activity; IEA:UniProtKB-KW.
DR GO; GO:0039653; P:suppression by virus of host transcription; IDA:UniProtKB.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0006351; P:transcription, DNA-templated; IEA:InterPro.
DR CDD; cd21557; Macro_X_Nsp3-like; 1.
DR Gene3D; 3.40.220.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR Gene3D; 3.40.50.300; -; 2.
DR Gene3D; 3.90.70.110; -; 1.
DR InterPro; IPR027351; (+)RNA_virus_helicase_core_dom.
DR InterPro; IPR002588; Alphavirus-like_MT_dom.
DR InterPro; IPR002620; Alphavirus_nsp2pro.
DR InterPro; IPR044936; Alphavirus_nsp2pro_sf.
DR InterPro; IPR043502; DNA/RNA_pol_sf.
DR InterPro; IPR002589; Macro_dom.
DR InterPro; IPR043472; Macro_dom-like.
DR InterPro; IPR044371; Macro_X_NSP3-like.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR007094; RNA-dir_pol_PSvirus.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR001788; Tymovirus_RNA-dep_RNA_pol.
DR Pfam; PF01661; Macro; 1.
DR Pfam; PF01707; Peptidase_C9; 1.
DR Pfam; PF00978; RdRP_2; 1.
DR Pfam; PF01443; Viral_helicase1; 1.
DR Pfam; PF01660; Vmethyltransf; 1.
DR SMART; SM00506; A1pp; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR SUPFAM; SSF52949; SSF52949; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF56672; SSF56672; 1.
DR PROSITE; PS51743; ALPHAVIRUS_MT; 1.
DR PROSITE; PS51154; MACRO; 1.
DR PROSITE; PS51520; NSP2PRO; 1.
DR PROSITE; PS51657; PSRV_HELICASE; 1.
DR PROSITE; PS50507; RDRP_SSRNA_POS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding;
KW Eukaryotic host gene expression shutoff by virus;
KW Eukaryotic host transcription shutoff by virus; GTP-binding; Helicase;
KW Host cell membrane; Host cell projection; Host cytoplasm;
KW Host cytoplasmic vesicle; Host gene expression shutoff by virus;
KW Host membrane; Host nucleus; Host-virus interaction; Hydrolase;
KW Inhibition of host innate immune response by virus;
KW Inhibition of host interferon signaling pathway by virus;
KW Inhibition of host RNA polymerase II by virus;
KW Inhibition of host STAT1 by virus; Lipoprotein; Membrane; Metal-binding;
KW Methyltransferase; mRNA capping; mRNA processing; Multifunctional enzyme;
KW Nucleotide-binding; Nucleotidyltransferase; Palmitate; Phosphoprotein;
KW Protease; Reference proteome; RNA suppression of termination; RNA-binding;
KW RNA-directed RNA polymerase; S-adenosyl-L-methionine; Thiol protease;
KW Transferase; Ubl conjugation; Viral immunoevasion; Viral RNA replication;
KW Zinc.
FT CHAIN 1..2513
FT /note="Polyprotein P1234"
FT /id="PRO_0000308405"
FT CHAIN 1..1903
FT /note="Polyprotein P123'"
FT /id="PRO_0000227771"
FT CHAIN 1..1896
FT /note="Polyprotein P123"
FT /id="PRO_0000227772"
FT CHAIN 1..540
FT /note="mRNA-capping enzyme nsP1"
FT /id="PRO_0000041236"
FT CHAIN 541..1347
FT /note="Protease nsP2"
FT /id="PRO_0000041237"
FT CHAIN 1348..1903
FT /note="Non-structural protein 3'"
FT /id="PRO_0000041238"
FT CHAIN 1348..1896
FT /note="Non-structural protein 3"
FT /id="PRO_0000227773"
FT CHAIN 1904..2513
FT /note="RNA-directed RNA polymerase nsP4"
FT /id="PRO_0000041239"
FT DOMAIN 30..260
FT /note="Alphavirus-like MT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01079"
FT DOMAIN 695..850
FT /note="(+)RNA virus helicase ATP-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00990"
FT DOMAIN 851..999
FT /note="(+)RNA virus helicase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00990"
FT DOMAIN 1012..1341
FT /note="Peptidase C9"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00853"
FT DOMAIN 1348..1507
FT /note="Macro"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00490"
FT DOMAIN 2267..2382
FT /note="RdRp catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT REGION 245..264
FT /note="NsP1 membrane-binding"
FT /evidence="ECO:0000250|UniProtKB:P08411"
FT REGION 1013..1032
FT /note="Nucleolus localization signal"
FT /evidence="ECO:0000250|UniProtKB:P08411"
FT REGION 1677..1705
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 1066..1075
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:P27282"
FT MOTIF 1196..1200
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:P08411"
FT MOTIF 1837..1840
FT /note="FGDF; binding to host G3BP1"
FT /evidence="ECO:0000250|UniProtKB:P08411"
FT MOTIF 1860..1863
FT /note="FGDF; binding to host G3BP1"
FT /evidence="ECO:0000250|UniProtKB:P08411"
FT ACT_SITE 1021
FT /note="For cysteine protease nsP2 activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00853"
FT ACT_SITE 1098
FT /note="For cysteine protease nsP2 activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00853"
FT BINDING 726..733
FT /ligand="a ribonucleoside 5'-triphosphate"
FT /ligand_id="ChEBI:CHEBI:61557"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00990"
FT BINDING 1371
FT /ligand="ADP-D-ribose"
FT /ligand_id="ChEBI:CHEBI:57967"
FT /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT BINDING 1379
FT /ligand="ADP-D-ribose"
FT /ligand_id="ChEBI:CHEBI:57967"
FT /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT BINDING 1459
FT /ligand="ADP-D-ribose"
FT /ligand_id="ChEBI:CHEBI:57967"
FT /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT BINDING 1460
FT /ligand="ADP-D-ribose"
FT /ligand_id="ChEBI:CHEBI:57967"
FT /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT BINDING 1461
FT /ligand="ADP-D-ribose"
FT /ligand_id="ChEBI:CHEBI:57967"
FT /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT BINDING 1610
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23010928"
FT BINDING 1612
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23010928"
FT BINDING 1635
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23010928"
FT BINDING 1653
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23010928"
FT SITE 39
FT /note="Involved in the phosphoramide link with 7-methyl-
FT GMP"
FT /evidence="ECO:0000250|UniProtKB:P27282"
FT SITE 540..541
FT /note="Cleavage; by protease nsP2"
FT /evidence="ECO:0000269|PubMed:2141206"
FT SITE 1347..1348
FT /note="Cleavage; by protease nsP2"
FT /evidence="ECO:0000269|PubMed:2141206"
FT SITE 1903..1904
FT /note="Cleavage; by protease nsP2"
FT /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT LIPID 420
FT /note="S-palmitoyl cysteine; by host"
FT /evidence="ECO:0000269|PubMed:10888610"
FT MUTAGEN 39
FT /note="H->A: Complete loss of methyl transferase activity
FT or viral infectivity."
FT /evidence="ECO:0000269|PubMed:8610444"
FT MUTAGEN 81
FT /note="H->A: Complete loss of methyl transferase activity
FT or viral infectivity."
FT /evidence="ECO:0000269|PubMed:8610444"
FT MUTAGEN 91
FT /note="D->A: Complete loss of methyl transferase activity
FT or viral infectivity."
FT /evidence="ECO:0000269|PubMed:8610444"
FT MUTAGEN 94
FT /note="R->A: Complete loss of methyl transferase activity
FT or viral infectivity."
FT /evidence="ECO:0000269|PubMed:8610444"
FT MUTAGEN 249
FT /note="Y->A: Complete loss of methyl transferase activity
FT or viral infectivity."
FT /evidence="ECO:0000269|PubMed:8610444"
FT MUTAGEN 369
FT /note="I->V: No effect on methyl transferase activity or
FT viral infectivity."
FT /evidence="ECO:0000269|PubMed:8610444"
FT MUTAGEN 420
FT /note="C->A: Complete loss of palmitoylation."
FT /evidence="ECO:0000269|PubMed:10888610"
FT MUTAGEN 539
FT /note="G->A: Partial loss of polyprotein processing between
FT nsp1 and nsp2."
FT /evidence="ECO:0000269|PubMed:2141206"
FT MUTAGEN 539
FT /note="G->E,V: Complete loss of polyprotein processing
FT between nsp1 and nsp2."
FT /evidence="ECO:0000269|PubMed:2141206"
FT MUTAGEN 703
FT /note="E->K: No effect on the synthesis and processing of
FT the polyproteins; blocks the conversion of the initial,
FT short-lived minus-strand replicase complex (RCinitial) into
FT the mature replicase and transcriptase complexes."
FT /evidence="ECO:0000269|PubMed:8627744"
FT MUTAGEN 815
FT /note="V->I: No effect on the synthesis and processing of
FT the polyproteins; blocks the conversion of the initial,
FT short-lived minus-strand replicase complex (RCinitial) into
FT the mature replicase and transcriptase complexes."
FT /evidence="ECO:0000269|PubMed:8627744"
FT MUTAGEN 956
FT /note="L->S: No effect on the synthesis and processing of
FT the polyproteins; blocks the conversion of the initial,
FT short-lived minus-strand replicase complex (RCinitial) into
FT the mature replicase and transcriptase complexes."
FT /evidence="ECO:0000269|PubMed:8627744"
FT MUTAGEN 1021
FT /note="C->A: Complete loss of nsP2 protease activity."
FT /evidence="ECO:0000269|PubMed:1448929"
FT MUTAGEN 1040
FT /note="C->W: NsP2 is only found in the nucleus."
FT /evidence="ECO:0000269|PubMed:30232189"
FT MUTAGEN 1098
FT /note="H->A: Complete loss of nsP2 protease activity."
FT /evidence="ECO:0000269|PubMed:1448929"
FT MUTAGEN 1099
FT /note="W->A: Complete loss of nsP2 protease activity."
FT /evidence="ECO:0000269|PubMed:1448929"
FT MUTAGEN 1159
FT /note="H->Q: Complete loss of nsP2-induced degradation of
FT host POLR2A; no effect on nsP2 localization."
FT /evidence="ECO:0000269|PubMed:30232189"
FT MUTAGEN 1183
FT /note="H->Q: Complete loss of nsP2-induced degradation of
FT host POLR2A; no effect on nsP2 localization."
FT /evidence="ECO:0000269|PubMed:30232189"
FT MUTAGEN 1223
FT /note="P->Q: NsP2 is only found in the nucleus."
FT /evidence="ECO:0000269|PubMed:30232189"
FT MUTAGEN 1224
FT /note="Q->P: Complete loss of nsP2-induced degradation of
FT host POLR2A; NsP2 is only found in the nucleus."
FT /evidence="ECO:0000269|PubMed:30232189"
FT MUTAGEN 1266
FT /note="P->G,L: Complete loss of nsP2-induced degradation of
FT host POLR2A, nsP2 is only found in the nucleus,."
FT /evidence="ECO:0000269|PubMed:22514352,
FT ECO:0000269|PubMed:30232189"
FT MUTAGEN 1346
FT /note="G->A: Partial loss of polyprotein processing between
FT nsp2 and nsp3."
FT /evidence="ECO:0000269|PubMed:2141206"
FT MUTAGEN 1346
FT /note="G->E,V: Complete loss of polyprotein processing
FT between nsp2 and nsp3."
FT /evidence="ECO:0000269|PubMed:2141206"
FT MUTAGEN 1610
FT /note="C->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23010928"
FT MUTAGEN 1612
FT /note="C->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23010928"
FT MUTAGEN 1635
FT /note="C->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23010928"
FT MUTAGEN 1653
FT /note="C->A: Complete loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23010928"
FT MUTAGEN 1896
FT /note="Y->YR,YS,YW: Reduces RNA synthesis in early phase of
FT infection."
FT /evidence="ECO:0000269|PubMed:2521676"
FT MUTAGEN 1904
FT /note="Y->A: No effect on nsP4 cleavage."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->C: Destabilizes nsP4."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->E: Reduces nsP4 cleavage."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->F: Destabilizes nsP4."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->L: Reduces nsP4 cleavage and destabilizes nsP4."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->M: Reduces nsP4 cleavage."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->N: Reduces nsP4 cleavage."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->P: Complete loss of nsP4 cleavage."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->Q: Reduces nsP4 cleavage."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->R: Destabilizes nsP4."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 1904
FT /note="Y->T: Reduces nsP4 cleavage."
FT /evidence="ECO:0000269|PubMed:9499091"
FT MUTAGEN 2368..2369
FT /note="DD->AA: Complete loss of RNA-directed RNA polymerase
FT activity."
FT /evidence="ECO:0000269|PubMed:19036396"
FT TURN 1013..1016
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1021..1032
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1039..1045
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1047..1050
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1057..1069
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1073..1075
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1079..1081
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1086..1088
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1098..1100
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1107..1109
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1112..1118
FT /evidence="ECO:0007829|PDB:4GUA"
FT TURN 1119..1121
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1124..1127
FT /evidence="ECO:0007829|PDB:4GUA"
FT TURN 1136..1138
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1141..1143
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1155..1159
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1174..1177
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1183..1188
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1198..1204
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1212..1214
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1217..1219
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1227..1232
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1242..1262
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1264..1275
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1280..1291
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1293..1299
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1310..1317
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1328..1338
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1351..1354
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1358..1360
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1363..1369
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1380..1387
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1389..1392
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1402..1407
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1410..1415
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1425..1445
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1449..1453
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1458..1460
FT /evidence="ECO:0007829|PDB:4GUA"
FT TURN 1461..1464
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1468..1479
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1485..1489
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1493..1507
FT /evidence="ECO:0007829|PDB:4GUA"
FT TURN 1531..1534
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1538..1541
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1543..1546
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1555..1567
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1571..1582
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1588..1593
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1609..1612
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1618..1626
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1632..1634
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1648..1650
FT /evidence="ECO:0007829|PDB:4GUA"
FT STRAND 1654..1656
FT /evidence="ECO:0007829|PDB:4GUA"
FT HELIX 1669..1672
FT /evidence="ECO:0007829|PDB:4GUA"
SQ SEQUENCE 2513 AA; 279661 MW; 8561459691FD395C CRC64;
MEKPVVNVDV DPQSPFVVQL QKSFPQFEVV AQQVTPNDHA NARAFSHLAS KLIELEVPTT
ATILDIGSAP ARRMFSEHQY HCVCPMRSPE DPDRMMKYAS KLAEKACKIT NKNLHEKIKD
LRTVLDTPDA ETPSLCFHND VTCNMRAEYS VMQDVYINAP GTIYHQAMKG VRTLYWIGFD
TTQFMFSAMA GSYPAYNTNW ADEKVLEARN IGLCSTKLSE GRTGKLSIMR KKELKPGSRV
YFSVGSTLYP EHRASLQSWH LPSVFHLNGK QSYTCRCDTV VSCEGYVVKK ITISPGITGE
TVGYAVTHNS EGFLLCKVTD TVKGERVSFP VCTYIPATIC DQMTGIMATD ISPDDAQKLL
VGLNQRIVIN GRTNRNTNTM QNYLLPIIAQ GFSKWAKERK DDLDNEKMLG TRERKLTYGC
LWAFRTKKVH SFYRPPGTQT CVKVPASFSA FPMSSVWTTS LPMSLRQKLK LALQPKKEEK
LLQVSEELVM EAKAAFEDAQ EEARAEKLRE ALPPLVADKG IEAAAEVVCE VEGLQADIGA
ALVETPRGHV RIIPQANDRM IGQYIVVSPN SVLKNAKLAP AHPLADQVKI ITHSGRSGRY
AVEPYDAKVL MPAGGAVPWP EFLALSESAT LVYNEREFVN RKLYHIAMHG PAKNTEEEQY
KVTKAELAET EYVFDVDKKR CVKKEEASGL VLSGELTNPP YHELALEGLK TRPAVPYKVE
TIGVIGTPGS GKSAIIKSTV TARDLVTSGK KENCREIEAD VLRLRGMQIT SKTVDSVMLN
GCHKAVEVLY VDEAFACHAG ALLALIAIVR PRKKVVLCGD PMQCGFFNMM QLKVHFNHPE
KDICTKTFYK YISRRCTQPV TAIVSTLHYD GKMKTTNPCK KNIEIDITGA TKPKPGDIIL
TCFRGWVKQL QIDYPGHEVM TAAASQGLTR KGVYAVRQKV NENPLYAITS EHVNVLLTRT
EDRLVWKTLQ GDPWIKQPTN IPKGNFQATI EDWEAEHKGI IAAINSPTPR ANPFSCKTNV
CWAKALEPIL ATAGIVLTGC QWSELFPQFA DDKPHSAIYA LDVICIKFFG MDLTSGLFSK
QSIPLTYHPA DSARPVAHWD NSPGTRKYGY DHAIAAELSR RFPVFQLAGK GTQLDLQTGR
TRVISAQHNL VPVNRNLPHA LVPEYKEKQP GPVKKFLNQF KHHSVLVVSE EKIEAPRKRI
EWIAPIGIAG ADKNYNLAFG FPPQARYDLV FINIGTKYRN HHFQQCEDHA ATLKTLSRSA
LNCLNPGGTL VVKSYGYADR NSEDVVTALA RKFVRVSAAR PDCVSSNTEM YLIFRQLDNS
RTRQFTPHHL NCVISSVYEG TRDGVGAAPS YRTKRENIAD CQEEAVVNAA NPLGRPGEGV
CRAIYKRWPT SFTDSATETG TARMTVCLGK KVIHAVGPDF RKHPEAEALK LLQNAYHAVA
DLVNEHNIKS VAIPLLSTGI YAAGKDRLEV SLNCLTTALD RTDADVTIYC LDKKWKERID
AALQLKESVT ELKDEDMEID DELVWIHPDS CLKGRKGFST TKGKLYSYFE GTKFHQAAKD
MAEIKVLFPN DQESNEQLCA YILGETMEAI REKCPVDHNP SSSPPKTLPC LCMYAMTPER
VHRLRSNNVK EVTVCSSTPL PKHKIKNVQK VQCTKVVLFN PHTPAFVPAR KYIEVPEQPT
APPAQAEEAP EVVATPSPST ADNTSLDVTD ISLDMDDSSE GSLFSSFSGS DNSITSMDSW
SSGPSSLEIV DRRQVVVADV HAVQEPAPIP PPRLKKMARL AAARKEPTPP ASNSSESLHL
SFGGVSMSLG SIFDGETARQ AAVQPLATGP TDVPMSFGSF SDGEIDELSR RVTESEPVLF
GSFEPGEVNS IISSRSAVSF PLRKQRRRRR SRRTEYXLTG VGGYIFSTDT GPGHLQKKSV
LQNQLTEPTL ERNVLERIHA PVLDTSKEEQ LKLRYQMMPT EANKSRYQSR KVENQKAITT
ERLLSGLRLY NSATDQPECY KITYPKPLYS SSVPANYSDP QFAVAVCNNY LHENYPTVAS
YQITDEYDAY LDMVDGTVAC LDTATFCPAK LRSYPKKHEY RAPNIRSAVP SAMQNTLQNV
LIAATKRNCN VTQMRELPTL DSATFNVECF RKYACNDEYW EEFARKPIRI TTEFVTAYVA
RLKGPKAAAL FAKTYNLVPL QEVPMDRFVM DMKRDVKVTP GTKHTEERPK VQVIQAAEPL
ATAYLCGIHR ELVRRLTAVL LPNIHTLFDM SAEDFDAIIA EHFKQGDPVL ETDIASFDKS
QDDAMALTGL MILEDLGVDQ PLLDLIECAF GEISSTHLPT GTRFKFGAMM KSGMFLTLFV
NTVLNVVIAS RVLEERLKTS RCAAFIGDDN IIHGVVSDKE MAERCATWLN MEVKIIDAVI
GERPPYFCGG FILQDSVTST ACRVADPLKR LFKLGKPLPA DDEQDEDRRR ALLDETKAWF
RVGITGTLAV AVTTRYEVDN ITPVLLALRT FAQSKRAFQA IRGEIKHLYG GPK
