ID   MTA_HHV8P               Reviewed;         455 AA.
AC   Q2HR75; O40938;
DT   03-NOV-2009, integrated into UniProtKB/Swiss-Prot.
DT   21-MAR-2006, sequence version 1.
DT   27-MAR-2024, entry version 78.
DE   RecName: Full=Post-transcriptional regulator MTA;
DE            Short=MTA;
DE   AltName: Full=EB2 protein homolog;
GN   ORFNames=ORF57;
OS   Human herpesvirus 8 type P (isolate GK18) (HHV-8) (Kaposi's
OS   sarcoma-associated herpesvirus).
OC   Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC   Herpesvirales; Orthoherpesviridae; Gammaherpesvirinae; Rhadinovirus;
OC   Rhadinovirus humangamma8; Human herpesvirus 8.
OX   NCBI_TaxID=868565;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=16760382; DOI=10.1099/vir.0.81919-0;
RA   Rezaee S.A.R., Cunningham C., Davison A.J., Blackbourn D.J.;
RT   "Kaposi's sarcoma-associated herpesvirus immune modulation: an overview.";
RL   J. Gen. Virol. 87:1781-1804(2006).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Neipel F., Albrecht J.-C., Ensser A., Huang Y.-Q., Li J.J.,
RA   Friedman-Kien A.E., Fleckenstein B.;
RT   "The genome of human herpesvirus 8 cloned from Kaposi's sarcoma.";
RL   Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   FUNCTION, AND INTERACTION WITH HUMAN ALYREF.
RX   PubMed=15155762; DOI=10.1074/jbc.m313008200;
RA   Malik P., Blackbourn D.J., Clements J.B.;
RT   "The evolutionarily conserved Kaposi's sarcoma-associated herpesvirus ORF57
RT   protein interacts with REF protein and acts as an RNA export factor.";
RL   J. Biol. Chem. 279:33001-33011(2004).
RN   [4]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=18184716; DOI=10.1128/jvi.01856-07;
RA   Majerciak V., Yamanegi K., Allemand E., Kruhlak M., Krainer A.R.,
RA   Zheng Z.M.;
RT   "Kaposi's sarcoma-associated herpesvirus ORF57 functions as a viral
RT   splicing factor and promotes expression of intron-containing viral lytic
RT   genes in spliceosome-mediated RNA splicing.";
RL   J. Virol. 82:2792-2801(2008).
RN   [5]
RP   REVIEW.
RX   PubMed=19273144; DOI=10.2741/3322;
RA   Majerciak V., Zheng Z.-M.;
RT   "Kaposi's sarcoma-associated herpesvirus ORF57 in viral RNA processing.";
RL   Front. Biosci. 14:1516-1528(2009).
RN   [6]
RP   SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF
RP   25-ASP--ASP-29; ASP-30 AND ASP-33.
RX   PubMed=20159985; DOI=10.1074/jbc.m109.068221;
RA   Majerciak V., Kruhlak M., Dagur P.K., McCoy J.P. Jr., Zheng Z.M.;
RT   "Caspase-7 cleavage of Kaposi sarcoma-associated herpesvirus ORF57 confers
RT   a cellular function against viral lytic gene expression.";
RL   J. Biol. Chem. 285:11297-11307(2010).
RN   [7]
RP   INTERACTION WITH PROTEIN KBZIP/K8.
RX   PubMed=23365430; DOI=10.1128/jvi.03459-12;
RA   Hunter O.V., Sei E., Richardson R.B., Conrad N.K.;
RT   "Chromatin immunoprecipitation and microarray analysis suggest functional
RT   cooperation between Kaposi's Sarcoma-associated herpesvirus ORF57 and K-
RT   bZIP.";
RL   J. Virol. 87:4005-4016(2013).
RN   [8]
RP   FUNCTION, INTERACTION WITH HOST PABPC1, AND SUBCELLULAR LOCATION.
RX   PubMed=23077296; DOI=10.1128/jvi.01693-12;
RA   Massimelli M.J., Majerciak V., Kruhlak M., Zheng Z.M.;
RT   "Interplay between polyadenylate-binding protein 1 and Kaposi's sarcoma-
RT   associated herpesvirus ORF57 in accumulation of polyadenylated nuclear RNA,
RT   a viral long noncoding RNA.";
RL   J. Virol. 87:243-256(2013).
RN   [9]
RP   FUNCTION, INTERACTION WITH HOST PRKRA AND EIF2AK2/PKR, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=29084250; DOI=10.1371/journal.ppat.1006677;
RA   Sharma N.R., Majerciak V., Kruhlak M.J., Zheng Z.M.;
RT   "KSHV inhibits stress granule formation by viral ORF57 blocking PKR
RT   activation.";
RL   PLoS Pathog. 13:e1006677-e1006677(2017).
RN   [10]
RP   FUNCTION.
RX   PubMed=30785952; DOI=10.1371/journal.ppat.1007596;
RA   Ruiz J.C., Hunter O.V., Conrad N.K.;
RT   "Kaposi's sarcoma-associated herpesvirus ORF57 protein protects viral
RT   transcripts from specific nuclear RNA decay pathways by preventing hMTR4
RT   recruitment.";
RL   PLoS Pathog. 15:e1007596-e1007596(2019).
RN   [11]
RP   FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH HOST AGO2 AND TNRC6A.
RX   PubMed=31400113; DOI=10.1093/nar/gkz683;
RA   Sharma N.R., Majerciak V., Kruhlak M.J., Yu L., Kang J.G., Yang A., Gu S.,
RA   Fritzler M.J., Zheng Z.M.;
RT   "KSHV RNA-binding protein ORF57 inhibits P-body formation to promote viral
RT   multiplication by interaction with Ago2 and GW182.";
RL   Nucleic Acids Res. 47:9368-9385(2019).
RN   [12] {ECO:0007744|PDB:5ZB1, ECO:0007744|PDB:5ZB3}
RP   X-RAY CRYSTALLOGRAPHY (3.06 ANGSTROMS) OF 168-455, SUBUNIT, SUBCELLULAR
RP   LOCATION, AND MUTAGENESIS OF TRP-292.
RX   PubMed=30096191; DOI=10.1371/journal.ppat.1007232;
RA   Yuan F., Gao Z.Q., Majerciak V., Bai L., Hu M.L., Lin X.X., Zheng Z.M.,
RA   Dong Y.H., Lan K.;
RT   "The crystal structure of KSHV ORF57 reveals dimeric active sites important
RT   for protein stability and function.";
RL   PLoS Pathog. 14:0-0(2018).
CC   -!- FUNCTION: Post-transcriptional regulator that plays an essential role
CC       in the expression of viral lytic genes and productive viral
CC       replication. Possesses numerous activities that promote the expression
CC       of viral genes including enhancement of RNA stability, promotion of RNA
CC       splicing and stimulation of protein translation often via its ability
CC       to interact with different cellular cofactors. Stabilizes
CC       polyadenylated nuclear (PAN) RNA by cooperative binding to a 9-nt core
CC       of the MRE (MTA responsive element) together with host PABPC1
CC       (PubMed:23077296). Functions as a viral splicing factor and promotes
CC       expression of intron-containing viral lytic genes (PubMed:18184716).
CC       Protects viral transcripts from specific nuclear RNA decay pathways by
CC       preventing host MTREX recruitment that promotes unwinding and
CC       degradation of structured RNA substrates (PubMed:30785952). Plays a
CC       role in the inhibition of host P-body formation by altering the
CC       scaffolding activity of TNRC6A at the initial stage thereby enhancing
CC       virus production (PubMed:31400113). Inhibits also host stress granule
CC       formation by blocking autophosphorylation of EIF2AK2/PKR and its
CC       subsequent binding to dsRNA (PubMed:29084250).
CC       {ECO:0000269|PubMed:18184716, ECO:0000269|PubMed:23077296,
CC       ECO:0000269|PubMed:29084250, ECO:0000269|PubMed:30785952,
CC       ECO:0000269|PubMed:31400113}.
CC   -!- SUBUNIT: Homodimer (PubMed:30096191). Homodimerization is required for
CC       transactivation (PubMed:30096191). Interacts with host ALYREF
CC       (PubMed:15155762). Associates in a complex with RNA, and host export
CC       factors NXF1/TAP and ALYREF; these interactions allow nuclear export of
CC       viral transcripts (PubMed:15155762). Interacts with protein K-bZIP/K8;
CC       this interaction promotes viral gene expression during lytic infection
CC       (PubMed:23365430). Interacts with host PABPC1 (PubMed:23077296).
CC       Interacts with host AGO2 and TNRC6A; these interactions inhibit host P-
CC       body formation (PubMed:31400113). Interacts with PRKRA and EIF2AK2/PKR;
CC       these interactions inhibit host stress granule formation
CC       (PubMed:29084250). {ECO:0000269|PubMed:15155762,
CC       ECO:0000269|PubMed:23077296, ECO:0000269|PubMed:23365430,
CC       ECO:0000269|PubMed:29084250, ECO:0000269|PubMed:30096191,
CC       ECO:0000269|PubMed:31400113}.
CC   -!- INTERACTION:
CC       Q2HR75; Q2HR82: K8; NbExp=5; IntAct=EBI-6884751, EBI-9006943;
CC       Q2HR75; Q86V81: ALYREF; Xeno; NbExp=4; IntAct=EBI-6884751, EBI-347640;
CC       Q2HR75; Q96QD9: FYTTD1; Xeno; NbExp=9; IntAct=EBI-6884751, EBI-724553;
CC       Q2HR75; Q9BRP8: PYM1; Xeno; NbExp=4; IntAct=EBI-6884751, EBI-2352802;
CC   -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000269|PubMed:20159985}.
CC       Host nucleus {ECO:0000269|PubMed:23077296, ECO:0000269|PubMed:29084250,
CC       ECO:0000269|PubMed:30096191, ECO:0000269|PubMed:31400113}.
CC       Note=Distributes in host nuclear splicing speckles.
CC       {ECO:0000269|PubMed:18184716}.
CC   -!- INDUCTION: Transactivated by ORF50 protein.
CC   -!- DOMAIN: Binds viral intronless RNAs. {ECO:0000250|UniProtKB:P10238}.
CC   -!- PTM: Proteolytically cleaved by host caspase-7 (CASP7), leading to its
CC       inactivation, thereby preventing expression of viral lytic genes.
CC       {ECO:0000269|PubMed:20159985}.
CC   -!- MISCELLANEOUS: ORF50 and ORF57 are the earliest genes expressed in the
CC       lytic cycle.
CC   -!- SIMILARITY: Belongs to the HHV-1 ICP27 protein family. {ECO:0000305}.
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DR   EMBL; AF148805; ABD28908.1; -; Genomic_DNA.
DR   EMBL; U93872; AAB62615.1; -; Genomic_DNA.
DR   RefSeq; YP_001129410.1; NC_009333.1.
DR   PDB; 5ZB1; X-ray; 3.06 A; A=168-455.
DR   PDB; 5ZB3; X-ray; 3.51 A; A/B=168-455.
DR   PDBsum; 5ZB1; -.
DR   PDBsum; 5ZB3; -.
DR   SMR; Q2HR75; -.
DR   BioGRID; 1777028; 141.
DR   IntAct; Q2HR75; 9.
DR   MINT; Q2HR75; -.
DR   DNASU; 4961525; -.
DR   GeneID; 4961525; -.
DR   KEGG; vg:4961525; -.
DR   Proteomes; UP000000942; Segment.
DR   GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; IEA:InterPro.
DR   InterPro; IPR008648; ICP27-like.
DR   Pfam; PF05459; Herpes_UL69; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Activator; Early protein; Host cytoplasm; Host nucleus;
KW   Metal-binding; Reference proteome; RNA-binding; Transcription;
KW   Transcription regulation; Zinc; Zinc-finger.
FT   CHAIN           1..455
FT                   /note="Post-transcriptional regulator MTA"
FT                   /id="PRO_0000387979"
FT   ZN_FING         333..432
FT                   /note="CHC2-type"
FT                   /evidence="ECO:0000250|UniProtKB:P10238"
FT   REGION          17..163
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           101..107
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   MOTIF           121..130
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   MOTIF           143..152
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        23..40
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        75..95
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        118..133
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         333
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P10238"
FT   BINDING         423
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P10238"
FT   BINDING         427
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P10238"
FT   BINDING         432
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P10238"
FT   SITE            33..34
FT                   /note="Cleavage; by host caspase-7"
FT                   /evidence="ECO:0000269|PubMed:20159985"
FT   MUTAGEN         25..29
FT                   /note="DESRD->AESRA: Does not affect cleavage by caspase-7
FT                   (CASP7)."
FT                   /evidence="ECO:0000269|PubMed:20159985"
FT   MUTAGEN         30
FT                   /note="D->A: Does not affect cleavage by caspase-7
FT                   (CASP7)."
FT                   /evidence="ECO:0000269|PubMed:20159985"
FT   MUTAGEN         33
FT                   /note="D->A: Abolished cleavage by caspase-7 (CASP7)."
FT                   /evidence="ECO:0000269|PubMed:20159985"
FT   MUTAGEN         292
FT                   /note="W->P: Complete loss of dimerization."
FT                   /evidence="ECO:0000269|PubMed:30096191"
FT   CONFLICT        1..16
FT                   /note="MVQAMIDMDIMKGILE -> RIVLSSSPGGPSPHPSFIAFDIT (in Ref.
FT                   2; AAB62615)"
FT                   /evidence="ECO:0000305"
FT   HELIX           197..199
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           224..230
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           236..239
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           243..248
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           250..257
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           263..276
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           279..298
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   STRAND          305..307
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           312..314
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           315..326
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           331..335
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           338..352
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   STRAND          353..355
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           357..366
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           372..387
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           388..391
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           394..405
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           411..423
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   TURN            424..426
FT                   /evidence="ECO:0007829|PDB:5ZB1"
FT   HELIX           430..439
FT                   /evidence="ECO:0007829|PDB:5ZB1"
SQ   SEQUENCE   455 AA;  51012 MW;  D3262C05AA472515 CRC64;
     MVQAMIDMDI MKGILEDSVS SSEFDESRDD ETDAPTLEDE QLSEPAEPPA DERIRGTQSA
     QGIPPPLGRI PKKSQGRSQL RSEIQFCSPL SRPRSPSPVN RYGKKIKFGT AGQNTRPPPE
     KRPRRRPRDR LQYGRTTRGG QCRAAPKRAT RRPQVNCQRQ DDDVRQGVSD AVKKLRLPAS
     MIIDGESPRF DDSIIPRHHG ACFNVFIPAP PSHVPEVFTD RDITALIRAG GKDDELINKK
     ISAKKIDHLH RQMLSFVTSR HNQAYWVSCR RETAAAGGLQ TLGAFVEEQM TWAQTVVRHG
     GWFDEKDIDI ILDTAIFVCN AFVTRFRLLH LSCVFDKQSE LALIKQVAYL VAMGNRLVEA
     CNLLGEVKLN FRGGLLLAFV LTIPGMQSRR SISARGQELF RTLLEYYRPG DVMGLLNVIV
     MEHHSLCRNS ECAAATRAAM GSAKFNKGLF FYPLS
//