ID   POLN_MAYAB              Reviewed;        2437 AA.
AC   Q8QZ73; Q8QHM4;
DT   04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT   10-APR-2019, sequence version 3.
DT   27-MAR-2024, entry version 132.
DE   RecName: Full=Polyprotein P1234;
DE            Short=P1234;
DE   AltName: Full=Non-structural 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:0000250|UniProtKB:P03317};
DE     AltName: Full=Non-structural protein 1;
DE   Contains:
DE     RecName: Full=Protease nsP2;
DE              EC=3.4.22.- {ECO:0000250|UniProtKB:Q8JUX6};
DE              EC=3.6.1.15 {ECO:0000250|UniProtKB:Q8JUX6};
DE              EC=3.6.1.74 {ECO:0000250|UniProtKB:P08411};
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:0000250|UniProtKB:P03317};
DE              EC=2.7.7.48 {ECO:0000255|PROSITE-ProRule:PRU00539};
DE     AltName: Full=Non-structural protein 4;
DE              Short=nsP4;
OS   Mayaro virus (strain Brazil) (MAYV).
OC   Viruses; Riboviria; Orthornavirae; Kitrinoviricota; Alsuviricetes;
OC   Martellivirales; Togaviridae; Alphavirus; Mayaro virus.
OX   NCBI_TaxID=374990;
OH   NCBI_TaxID=7159; Aedes aegypti (Yellowfever mosquito) (Culex aegypti).
OH   NCBI_TaxID=7180; Haemagogus.
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RA   Netto M.C.M.G., Shirako Y., Strauss E.G., Carvalho M.G.C., Strauss J.H.;
RL   Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases.
RN   [2] {ECO:0007744|PDB:5IQ5}
RP   STRUCTURE BY NMR OF 1335-1493.
RX   PubMed=25217003; DOI=10.1007/s12104-014-9572-0;
RA   Melekis E., Tsika A.C., Lichiere J., Chasapis C.T., Margiolaki I.,
RA   Papageorgiou N., Coutard B., Bentrop D., Spyroulias G.A.;
RT   "NMR study of non-structural proteins--part I: (1)H, (13)C, (15)N backbone
RT   and side-chain resonance assignment of macro domain from Mayaro virus
RT   (MAYV).";
RL   Biomol. NMR. Assign. 9:191-195(2015).
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 (By
CC       similarity). As soon P123 is cleaved into mature proteins, the plus-
CC       strand RNAs synthesis begins (By similarity).
CC       {ECO:0000250|UniProtKB:P03317}.
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}.
CC   -!- FUNCTION: [mRNA-capping enzyme nsP1]: Cytoplasmic capping enzyme that
CC       catalyzes two virus-specific reactions: methyltransferase and nsP1
CC       guanylyltransferase (By similarity). 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 (By similarity). nsP1 capping consists in the following reactions:
CC       GTP is first methylated into 7-methyl-GMP and then is covalently linked
CC       to nsP1 to form the m7GMp-nsP1 complex from which 7-methyl-GMP complex
CC       is transferred to the mRNA to create the cap structure (By similarity).
CC       NsP1 is needed for the initiation of the minus-strand RNAs synthesis
CC       (By similarity). 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:P03317,
CC       ECO:0000250|UniProtKB:P08411, ECO:0000250|UniProtKB:Q8JUX6,
CC       ECO:0000305}.
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 (By similarity). 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 (By similarity). The resulting inhibition of
CC       cellular protein synthesis serves to ensure maximal viral gene
CC       expression and to evade host immune response (By similarity).
CC       {ECO:0000250|UniProtKB:P03317, ECO:0000250|UniProtKB:P08411,
CC       ECO:0000250|UniProtKB:Q8JUX6}.
CC   -!- FUNCTION: [Non-structural protein 3']: Seems to be essential for minus-
CC       strand RNAs and subgenomic 26S mRNAs synthesis (By similarity).
CC       Displays mono-ADP-ribosylhydrolase activity (Probable). ADP-
CC       ribosylation is a post-translational modification that controls various
CC       processes of the host cell and the virus probably needs to revert it
CC       for optimal viral replication (Probable). Binds proteins of FXR family
CC       and sequesters them into the viral RNA replication complexes thereby
CC       inhibiting the formation of host stress granules on viral mRNAs
CC       (Probable). The nsp3'-FXR complexes bind viral RNAs and probably
CC       orchestrate the assembly of viral replication complexes, thanks to the
CC       ability of FXR family members to self-assemble and bind DNA (Probable).
CC       {ECO:0000250|UniProtKB:P03317, ECO:0000305}.
CC   -!- FUNCTION: [Non-structural protein 3]: Seems to be essential for minus-
CC       strand RNAs and subgenomic 26S mRNAs synthesis (By similarity).
CC       Displays mono-ADP-ribosylhydrolase activity (By similarity). 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 (By similarity). Binds proteins
CC       of G3BP family and sequesters them into the viral RNA replication
CC       complexes thereby inhibiting the formation of host stress granules on
CC       viral mRNAs (By similarity). The nsp3-G3BP complexes bind viral RNAs
CC       and probably orchestrate the assembly of viral replication complexes,
CC       thanks to the ability of G3BP family members to self-assemble and bind
CC       DNA (By similarity). {ECO:0000250|UniProtKB:P03317,
CC       ECO:0000250|UniProtKB:Q8JUX6}.
CC   -!- FUNCTION: [RNA-directed RNA polymerase nsP4]: RNA dependent RNA
CC       polymerase (By similarity). Replicates genomic and antigenomic RNA by
CC       recognizing replications specific signals. The early replication
CC       complex formed by the polyprotein P123 and nsP4 synthesizes minus-
CC       strand RNAs (By similarity). The late replication complex composed of
CC       fully processed nsP1-nsP4 is responsible for the production of genomic
CC       and subgenomic plus-strand RNAs (By similarity). The core catalytic
CC       domain of nsP4 also possesses terminal adenylyltransferase (TATase)
CC       activity that is probably involved in maintenance and repair of the
CC       poly(A) tail, an element required for replication of the viral genome
CC       (By similarity). {ECO:0000250|UniProtKB:P03317}.
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=L-histidyl-[protein] + N(7)-methyl-GTP = diphosphate +
CC         N(tele)-(N(7)-methylguanosine 5'-phospho)-L-histidyl-[protein];
CC         Xref=Rhea:RHEA:54792, Rhea:RHEA-COMP:9745, Rhea:RHEA-COMP:13995,
CC         ChEBI:CHEBI:29979, ChEBI:CHEBI:33019, ChEBI:CHEBI:87133,
CC         ChEBI:CHEBI:138334; Evidence={ECO:0000250|UniProtKB:P03317};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54793;
CC         Evidence={ECO:0000250|UniProtKB:P03317};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end diphospho-(purine-ribonucleoside) in mRNA + H(+) +
CC         N(tele)-(N(7)-methylguanosine 5'-phospho)-L-histidyl-[protein] = a
CC         5'-end (N(7)-methyl 5'-triphosphoguanosine)-(purine-ribonucleoside)
CC         in mRNA + L-histidyl-[protein]; Xref=Rhea:RHEA:54800, Rhea:RHEA-
CC         COMP:9745, Rhea:RHEA-COMP:12925, Rhea:RHEA-COMP:13929, Rhea:RHEA-
CC         COMP:13995, ChEBI:CHEBI:15378, ChEBI:CHEBI:29979, ChEBI:CHEBI:133968,
CC         ChEBI:CHEBI:138276, ChEBI:CHEBI:138334;
CC         Evidence={ECO:0000250|UniProtKB:P27282};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end triphospho-ribonucleoside in mRNA + H2O = a 5'-end
CC         diphospho-ribonucleoside in mRNA + H(+) + phosphate;
CC         Xref=Rhea:RHEA:67004, Rhea:RHEA-COMP:17164, Rhea:RHEA-COMP:17165,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474,
CC         ChEBI:CHEBI:167616, ChEBI:CHEBI:167618; EC=3.6.1.74;
CC         Evidence={ECO:0000250|UniProtKB:P08411};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67005;
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   -!- 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:0000250|UniProtKB:P03317};
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:0000250|UniProtKB:P03317};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54429;
CC         Evidence={ECO:0000250|UniProtKB:P03317};
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:0000250|UniProtKB:P03317};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58249;
CC         Evidence={ECO:0000250|UniProtKB:P03317};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ADP-alpha-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:0000250|UniProtKB:P03317};
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000250|UniProtKB:P03317};
CC       Note=For nsP4 adenylyltransferase activity; Mn(2+) supports catalysis
CC       at 60% of the levels observed with Mg(2+).
CC       {ECO:0000250|UniProtKB:P03317};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:P03317};
CC       Note=For nsP4 RNA-directed RNA polymerase activity.
CC       {ECO:0000250|UniProtKB:P03317};
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   -!- 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:P03317,
CC       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       (By similarity). 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 (By
CC       similarity). {ECO:0000250|UniProtKB:P03317,
CC       ECO:0000250|UniProtKB:P27282}.
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:P03317, 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:P03317,
CC       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:0000250|UniProtKB:P03317}; 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 (By
CC       similarity). 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 (By
CC       similarity). {ECO:0000250|UniProtKB:P03317}.
CC   -!- SUBCELLULAR LOCATION: [Non-structural protein 3']: Host cytoplasmic
CC       vesicle membrane {ECO:0000250|UniProtKB:P03317}; 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 (By
CC       similarity). 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 (By
CC       similarity). {ECO:0000250|UniProtKB:P03317}.
CC   -!- SUBCELLULAR LOCATION: [RNA-directed RNA polymerase nsP4]: Host
CC       cytoplasmic vesicle membrane; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:P03317}. 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 (By similarity). The
CC       central part has a zinc-binding function (By similarity). 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:P03317, ECO:0000250|UniProtKB:P08411}.
CC   -!- DOMAIN: [Non-structural protein 3']: In the N-terminus, the macro
CC       domain displays a mono-ADP-ribosylhydrolase activity (By similarity).
CC       The central part has a zinc-binding function (By similarity). 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:P03317, ECO:0000250|UniProtKB:P08411}.
CC   -!- PTM: [Polyprotein P1234]: Specific enzymatic cleavages in vivo yield
CC       mature proteins (By similarity). The processing of the polyprotein is
CC       temporally regulated (By similarity). In early stages (1.7 hpi), P1234
CC       is first cleaved in trans through its nsP2 protease activity, releasing
CC       P123' and nsP4, which associate to form the early replication complex
CC       (By similarity). At the same time, P1234 is also cut at the nsP1/nsP2
CC       site early in infection but with lower efficiency (By similarity).
CC       After replication of the viral minus-strand RNAs (4 hpi), the
CC       polyproteins are cut at the nsP1/nsP2 and nsP2/nsP3 sites very
CC       efficiently, preventing accumulation of P123' and P1234 and allowing
CC       the formation of the late replication complex (By similarity).
CC       NsP3'/nsP4 site is not cleaved anymore and P34 is produced rather than
CC       nsP4 (By similarity). {ECO:0000250|UniProtKB:P03317}.
CC   -!- PTM: [Polyprotein P123]: Specific enzymatic cleavages in vivo yield
CC       mature proteins (By similarity). The processing of the polyprotein is
CC       temporally regulated (By similarity). In early stages (1.7 hpi), P123
CC       is cleaved at the nsP1/nsP2 site with low efficiency (By similarity).
CC       After replication of the viral minus-strand RNAs (4 hpi), the
CC       polyproteins are cut at the nsP1/nsP2 and nsP2/nsP3 sites very
CC       efficiently, preventing accumulation of P123 and allowing the formation
CC       of the late replication complex (By similarity).
CC       {ECO:0000250|UniProtKB:P03317}.
CC   -!- PTM: [Polyprotein P123']: Specific enzymatic cleavages in vivo yield
CC       mature proteins (By similarity). The processing of the polyprotein is
CC       temporally regulated (By similarity). In early stages (1.7 hpi), P123'
CC       is cleaved at the nsP1/nsP2 site with low efficiency (By similarity).
CC       After replication of the viral minus-strand RNAs (4 hpi), the
CC       polyproteins are cut at the nsP1/nsP2 and nsP2/nsP3 sites very
CC       efficiently, preventing accumulation of P123' and allowing the
CC       formation of the late replication complex (By similarity).
CC       {ECO:0000250|UniProtKB:P03317}.
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 (By similarity).
CC       Nsp4 is present in extremely low quantities due to low frequency of
CC       translation through the amber stop-codon and the degradation by the
CC       ubiquitin pathway (By similarity). {ECO:0000250|UniProtKB:P03317}.
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 (By similarity).
CC       This inactivates completely cellular translation initiation, resulting
CC       shutoff of host proteins synthesis (By similarity). However,
CC       phosphorylation of EIF2A is probably not the only mechanism responsible
CC       for the host translation shutoff (By similarity). The viral translation
CC       can still occur normally because it relies on a hairpin structure in
CC       the coding region of sgRNA and is EIF2A-, EIF2D-, EIF4G- EIF4A-
CC       independent (By similarity). {ECO:0000250|UniProtKB:P03317}.
CC   -!- MISCELLANEOUS: The genome codes for P123, but readthrough of a
CC       terminator codon UGA occurs between the codons for Ser-1819 and Leu-
CC       1821 giving rise to P1234 (Probable). P1234 is cleaved quickly by nsP2
CC       into P123' and nsP4 (By similarity). Further processing of p123' gives
CC       nsP1, nsP2 and nsP3' which is 6 amino acids longer than nsP3 since the
CC       cleavage site is after the readthrough (By similarity). This unusual
CC       molecular mechanism ensures that few nsP4 are produced compared to
CC       other non-structural proteins (By similarity). Mutant viruses with no
CC       alternative termination site grow significantly slower than wild-type
CC       virus (By similarity). The opal termination codon is frequently mutated
CC       to a sense codon on passage in cell culture (By similarity). The
CC       presence of the opal codon may be a requirement for viral maintenance
CC       in both vertebrate and invertebrate hosts and a selective advantage may
CC       be conferred in cell culture for the sense codon (By similarity).
CC       {ECO:0000250|UniProtKB:O90368, ECO:0000250|UniProtKB:P03317,
CC       ECO:0000305}.
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DR   EMBL; AF237947; AAL79763.1; -; Genomic_RNA.
DR   EMBL; AF237947; AAL79765.1; ALT_SEQ; Genomic_RNA.
DR   RefSeq; NP_579968.1; NC_003417.1.
DR   RefSeq; NP_579969.1; NC_003417.1.
DR   PDB; 5IQ5; NMR; -; A=1335-1493.
DR   PDBsum; 5IQ5; -.
DR   SMR; Q8QZ73; -.
DR   IntAct; Q8QZ73; 5.
DR   MEROPS; C09.001; -.
DR   GeneID; 935140; -.
DR   GeneID; 935142; -.
DR   KEGG; vg:935140; -.
DR   KEGG; vg:935142; -.
DR   Proteomes; UP000007774; Segment.
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: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:0140818; F:mRNA 5'-phosphatase activity; IEA:RHEA.
DR   GO; GO:0008174; F:mRNA methyltransferase activity; IEA:InterPro.
DR   GO; GO:1990817; F:poly(A) RNA polymerase activity; IEA:UniProtKB-EC.
DR   GO; GO:0004651; F:polynucleotide 5'-phosphatase 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-dependent RNA polymerase activity; IEA:UniProtKB-KW.
DR   GO; GO:0006370; P:7-methylguanosine mRNA capping; IEA:UniProtKB-KW.
DR   GO; GO:0006351; P:DNA-templated transcription; IEA:InterPro.
DR   GO; GO:0006508; P:proteolysis; 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:0039694; P:viral RNA genome replication; IEA:InterPro.
DR   CDD; cd21557; Macro_X_Nsp3-like; 1.
DR   CDD; cd23250; Togaviridae_RdRp; 1.
DR   Gene3D; 3.90.70.110; Alphavirus nsP2 protease domain; 1.
DR   Gene3D; 3.40.220.10; Leucine Aminopeptidase, subunit E, domain 1; 1.
DR   Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2.
DR   Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 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; IPR048891; nsP3_ZBD.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   InterPro; IPR001788; RNA-dep_RNA_pol_alsuvir.
DR   InterPro; IPR007094; RNA-dir_pol_PSvirus.
DR   InterPro; IPR029063; SAM-dependent_MTases_sf.
DR   InterPro; IPR047311; Togaviridae_RdRp.
DR   InterPro; IPR049329; ToMV_Hel_N.
DR   PANTHER; PTHR11106:SF27; ADP-RIBOSE GLYCOHYDROLASE MACROD2; 1.
DR   PANTHER; PTHR11106; GANGLIOSIDE INDUCED DIFFERENTIATION ASSOCIATED PROTEIN 2-RELATED; 1.
DR   Pfam; PF01661; Macro; 1.
DR   Pfam; PF20852; nsP3_ZBD; 1.
DR   Pfam; PF01707; Peptidase_C9; 1.
DR   Pfam; PF00978; RdRP_2; 1.
DR   Pfam; PF20896; ToMV_Hel_N; 1.
DR   Pfam; PF01443; Viral_helicase1; 1.
DR   Pfam; PF01660; Vmethyltransf; 1.
DR   SMART; SM00506; A1pp; 1.
DR   SUPFAM; SSF56672; DNA/RNA polymerases; 1.
DR   SUPFAM; SSF52949; Macro domain-like; 1.
DR   SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1.
DR   SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 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 RNA polymerase II by virus; Lipoprotein; Membrane;
KW   Metal-binding; Methyltransferase; mRNA capping; mRNA processing;
KW   Multifunctional enzyme; Nucleotide-binding; Nucleotidyltransferase;
KW   Palmitate; Protease; RNA suppression of termination; RNA-binding;
KW   RNA-directed RNA polymerase; S-adenosyl-L-methionine; Thiol protease;
KW   Transferase; Ubl conjugation; Viral RNA replication; Zinc.
FT   CHAIN           1..2437
FT                   /note="Polyprotein P1234"
FT                   /id="PRO_0000308393"
FT   CHAIN           1..1826
FT                   /note="Polyprotein P123'"
FT                   /id="PRO_0000229927"
FT   CHAIN           1..1819
FT                   /note="Polyprotein P123"
FT                   /id="PRO_0000229926"
FT   CHAIN           1..536
FT                   /note="mRNA-capping enzyme nsP1"
FT                   /id="PRO_0000229928"
FT   CHAIN           537..1334
FT                   /note="Protease nsP2"
FT                   /id="PRO_0000229929"
FT   CHAIN           1335..1826
FT                   /note="Non-structural protein 3'"
FT                   /id="PRO_0000229931"
FT   CHAIN           1335..1819
FT                   /note="Non-structural protein 3"
FT                   /id="PRO_0000229930"
FT   CHAIN           1827..2437
FT                   /note="RNA-directed RNA polymerase nsP4"
FT                   /id="PRO_0000229932"
FT   DOMAIN          28..259
FT                   /note="Alphavirus-like MT"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01079"
FT   DOMAIN          691..843
FT                   /note="(+)RNA virus helicase ATP-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00990"
FT   DOMAIN          844..992
FT                   /note="(+)RNA virus helicase C-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00990"
FT   DOMAIN          1005..1327
FT                   /note="Peptidase C9"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00853"
FT   DOMAIN          1335..1493
FT                   /note="Macro"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00490"
FT   DOMAIN          2191..2306
FT                   /note="RdRp catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT   REGION          244..263
FT                   /note="NsP1 membrane-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P08411"
FT   REGION          1006..1025
FT                   /note="Nucleolus localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:P08411"
FT   REGION          1680..1735
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           1059..1068
FT                   /note="Nuclear export signal"
FT                   /evidence="ECO:0000250|UniProtKB:P27282"
FT   MOTIF           1182..1186
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:P08411"
FT   MOTIF           1792..1795
FT                   /note="FGDF; binding to host G3BP1"
FT                   /evidence="ECO:0000250|UniProtKB:P08411"
FT   MOTIF           1804..1807
FT                   /note="FGDF; binding to host G3BP1"
FT                   /evidence="ECO:0000250|UniProtKB:P08411"
FT   COMPBIAS        1688..1703
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        1014
FT                   /note="For cysteine protease nsP2 activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00853"
FT   ACT_SITE        1084
FT                   /note="For cysteine protease nsP2 activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00853"
FT   BINDING         722..729
FT                   /ligand="a ribonucleoside 5'-triphosphate"
FT                   /ligand_id="ChEBI:CHEBI:61557"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00990"
FT   BINDING         1344
FT                   /ligand="ADP-D-ribose"
FT                   /ligand_id="ChEBI:CHEBI:57967"
FT                   /evidence="ECO:0000250|UniProtKB:P36328"
FT   BINDING         1358
FT                   /ligand="ADP-D-ribose"
FT                   /ligand_id="ChEBI:CHEBI:57967"
FT                   /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT   BINDING         1366
FT                   /ligand="ADP-D-ribose"
FT                   /ligand_id="ChEBI:CHEBI:57967"
FT                   /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT   BINDING         1446
FT                   /ligand="ADP-D-ribose"
FT                   /ligand_id="ChEBI:CHEBI:57967"
FT                   /evidence="ECO:0000250|UniProtKB:P36328"
FT   BINDING         1447
FT                   /ligand="ADP-D-ribose"
FT                   /ligand_id="ChEBI:CHEBI:57967"
FT                   /evidence="ECO:0000250|UniProtKB:P36328"
FT   BINDING         1448
FT                   /ligand="ADP-D-ribose"
FT                   /ligand_id="ChEBI:CHEBI:57967"
FT                   /evidence="ECO:0000250|UniProtKB:P36328"
FT   BINDING         1596
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P03317"
FT   BINDING         1598
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P03317"
FT   BINDING         1621
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P03317"
FT   BINDING         1639
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P03317"
FT   SITE            37
FT                   /note="Involved in the phosphoramide link with 7-methyl-
FT                   GMP"
FT                   /evidence="ECO:0000250|UniProtKB:P27282"
FT   SITE            536..537
FT                   /note="Cleavage; by protease nsP2"
FT                   /evidence="ECO:0000250|UniProtKB:P03317"
FT   SITE            1334..1335
FT                   /note="Cleavage; by protease nsP2"
FT                   /evidence="ECO:0000250|UniProtKB:P03317"
FT   SITE            1826..1827
FT                   /note="Cleavage; by protease nsP2"
FT                   /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT   LIPID           417
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT   LIPID           419
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q8JUX6"
FT   STRAND          1337..1344
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   STRAND          1350..1357
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   HELIX           1369..1374
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   HELIX           1376..1379
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   STRAND          1389..1403
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   HELIX           1407..1409
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   HELIX           1412..1433
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   STRAND          1436..1441
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   HELIX           1455..1466
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   STRAND          1471..1477
FT                   /evidence="ECO:0007829|PDB:5IQ5"
FT   HELIX           1481..1492
FT                   /evidence="ECO:0007829|PDB:5IQ5"
SQ   SEQUENCE   2437 AA;  271996 MW;  B43A8C61A8B31829 CRC64;
     MSKVFVDIEA ESPFLKSLQR AFPAFEVEAQ QVTPNDHANA RAFSHLATKL IEQETEKDTL
     ILDIGSAPAR RMMSEHTYHC VCPMRSAEDP ERLLYYARKL AKASGEVVDR NIAAKIDDLQ
     SVMATPDNES RTFCLHTDQT CRTQAEVAVY QDVYAVHAPT SLYFQAMKGV RTAYWIGFDT
     TPFMFDTMAG AYPTYATNWA DEQVLKARNI GLCSASLTEG HLGKLSIMRK KKMTPSDQIM
     FSVGSTLYIE SRRLLKSWHL PSVFHLKGRQ SYTCRCDTIV SCEGYVVKKI TMSPGVFGKT
     SGYAVTHHAE GFLVCKTTDT IAGERVSFPI CTYVPSTICD QMTGILATEV TPEDAQKLLV
     GLNQRIVVNG RTQRNTNTMK NYLLPVVSQA FSKWAKEYRL DQEDEKNMGM RERTLTCCCL
     WAFKTHKNHT MYKKPDTQTI VKVPSEFNSF VIPSLWSAGL SIGIRHRIRL LLQSRRVEPL
     VPSMDVGEAR AAEREAAEAK EAEDTLAALP PLIPTAPVLD DIPEVDVEEL EFRAGAGVVE
     TPRNALKVTP QDRDTMVGSY LVLSPQTVLK SVKLQALHPL AESVKIITHK GRAGRYQVDA
     YDGRVLLPTG AAIPVPDFQA LSESATMVYN EREFINRKLY HIAVHGAALN TDEEGYEKVR
     AESTDAEYVY DVDRKQCVKR EEAEGLVMIG DLINPPFHEF AYEGLKRRPA APYKTTVVGV
     FGVPGSGKSG IIKSLVTRGD LVASGKKENC QEIMLDVKRY RDLDMTAKTV DSVLLNGVKQ
     TVDVLYVDEA FACHAGTLLA LIATVRPRKK VVLCGDPKQC GFFNLMQLQV NFNHNICTEV
     DHKSISRRCT LPITAIVSTL HYEGRMRTTN PYNKPVIIDT TGQTKPNRED IVLTCFRGWV
     KQLQLDYRGH EVMTAAASQG LTRKGVYAVR MKVNENPLYA QSSEHVNVLL TRTEGRLVWK
     TLSGDPWIKT LSNIPKGNFT ATLEDWQREH DTIMRAITQE AAPLDVFQNK AKVCWAKCLV
     PVLETAGIKL SATDWSAIIL AFKEDRAYSP EVALNEICTK IYGVDLDSGL FSAPRVSLHY
     TTNHWDNSPG GRMYGFSVEA ANRLEQQHPF YRGRWASGQV LVAERKTQPI DVTCNLIPFN
     RRLPHTLVTE YHPIKGERVE WLVNKIPGYH VLLVSEYNLI LPRRKVTWIA PPTVTGADLT
     YDLDLGLPPN AGRYDLVFVN MHTPYRLHHY QQCVDHAMKL QMLGGDALYL LKPGGSLLLS
     TYAYADRTSE AVVTALARRF SSFRAVTVRC VTSNTEVFLL FTNFDNGRRT VTLHQTNGKL
     SSIYAGTVLQ AAGCAPAYAV KRADIATAIE DAVVNAANHR GQVGDGVCRA VARKWPQAFR
     NAATPVGTAK TVKCDETYII HAVGPNFNNT SEAEGDRDLA AAYRAVAAEI NRLSISSVAI
     PLLSTGIFSA GKDRVHQSLS HLLAAMDTTE ARVTIYCRDK TWEQKIKTVL QNRSATELVS
     DELQFEVNLT RVHPDSSLVG RPGYSTTDGT LYSYMEGTKF HQAALDMAEI TTLWPRVQDA
     NEHICLYALG ETMDNIRARC PVEDSDSSTP PKTVPCLCRY AMTPERVTRL RMHHTKDFVV
     CSSFQLPKYR IPGVQRVKCE KVMLFDAAPP ASVSPVQYLT NQSETTISLS SFSITSDSSS
     LSTFPDLESA EELDHDSQSV RPALNEPDDH QPTPTAELAT HPVPPPRPNR ARRLAAARVQ
     VQVEVHQPPS NQPTKPIPAP RTSLRPVPAP RRYVPRPVVE LPWPLETIDV EFGAPTEEES
     DITFGDFSAS EWETISNSSX LGRAGAYIFS SDVGPGHLQQ KSVRQHDLEV PIMDRVIEEK
     VYPPKLDEAK EKQLLLKLQM HATDANRSRY QSRKVENMKA TIIDRLKQGS AYYVSAAADK
     AVTYHVRYAK PRYSVPVMQR LSSATIAVAT CNEFLARNYP TVASYQITDE YDAYLDMVDG
     SESCLDRANF CPAKLRCYPK HHAYHMPQIR SAVPSPFQNT LQNVLAAATK RNCNVTQMRE
     LPTLDSAVYN VECFRKYACN NEYWEEFAKK PIRITTENLT TYVTKLKGGK AAALFAKTHN
     LVPLQEVPMD RFIMDMKRDV KVTPGTKHTE ERPKVQVIQA AEPLATAYLC GIHRELVRRL
     NAVLLPNIHT LFDMSAEDFD AIISEHFKPG DHVLETDIAS FDKSQDDSLA LTGLMILEDL
     GVDNQLLDLI EAAFGQITSC HLPTGTRFKF GAMMKSGMFL TLFINTVLNI TIASRVLEAR
     LTNSACAAFI GDDNVVHGVV SDKLMADRCA TWVNMEVKII DAVMCIKPPY FCGGFLVYDH
     VTRTACRIAD PLKRLFKLGK PLPADDCQDE DRRRALYDEV KKWSRSGLGS EIEVALASRY
     RLEGSYNLLL AMSTFAHSMK NFSALRGPVI HLYGGPK
//