MTA70_DROME
ID MTA70_DROME Reviewed; 608 AA.
AC Q9VCE6;
DT 25-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=N6-adenosine-methyltransferase MT-A70-like protein;
DE EC=2.1.1.348 {ECO:0000250|UniProtKB:Q86U44};
DE AltName: Full=Inducer of meiosis 4 {ECO:0000303|PubMed:27919081, ECO:0000303|PubMed:28675155};
DE AltName: Full=Methyltransferase-like 3 {ECO:0000312|FlyBase:FBgn0039139};
GN Name=Mettl3 {ECO:0000303|PubMed:21873203, ECO:0000312|FlyBase:FBgn0039139};
GN Synonyms=Ime4 {ECO:0000303|PubMed:27919081, ECO:0000303|PubMed:28675155};
GN ORFNames=CG5933 {ECO:0000312|FlyBase:FBgn0039139};
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley;
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [2]
RP GENOME REANNOTATION.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley; TISSUE=Testis;
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE,
RP AND MUTAGENESIS OF ASP-413 AND TRP-416.
RX PubMed=21873203; DOI=10.1073/pnas.1111577108;
RA Hongay C.F., Orr-Weaver T.L.;
RT "Drosophila Inducer of MEiosis 4 (IME4) is required for Notch signaling
RT during oogenesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:14855-14860(2011).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, DEVELOPMENTAL STAGE,
RP AND IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=27919077; DOI=10.1038/nature20568;
RA Lence T., Akhtar J., Bayer M., Schmid K., Spindler L., Ho C.H., Kreim N.,
RA Andrade-Navarro M.A., Poeck B., Helm M., Roignant J.Y.;
RT "m(6)A modulates neuronal functions and sex determination in Drosophila.";
RL Nature 540:242-247(2016).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=27919081; DOI=10.1038/nature20577;
RA Haussmann I.U., Bodi Z., Sanchez-Moran E., Mongan N.P., Archer N.,
RA Fray R.G., Soller M.;
RT "m(6)A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila
RT sex determination.";
RL Nature 540:301-304(2016).
RN [7]
RP IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=29535189; DOI=10.1101/gad.309146.117;
RA Knuckles P., Lence T., Haussmann I.U., Jacob D., Kreim N., Carl S.H.,
RA Masiello I., Hares T., Villasenor R., Hess D., Andrade-Navarro M.A.,
RA Biggiogera M., Helm M., Soller M., Buehler M., Roignant J.Y.;
RT "Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-
RT binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d.";
RL Genes Dev. 32:415-429(2018).
RN [8]
RP FUNCTION, IDENTIFICATION IN THE WMM COMPLEX, SUBCELLULAR LOCATION, AND
RP DISRUPTION PHENOTYPE.
RX PubMed=28675155; DOI=10.1038/ncomms15737;
RA Kan L., Grozhik A.V., Vedanayagam J., Patil D.P., Pang N., Lim K.S.,
RA Huang Y.C., Joseph B., Lin C.J., Despic V., Guo J., Yan D., Kondo S.,
RA Deng W.M., Dedon P.C., Jaffrey S.R., Lai E.C.;
RT "The m6A pathway facilitates sex determination in Drosophila.";
RL Nat. Commun. 8:15737-15737(2017).
RN [9]
RP IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=29555755; DOI=10.1073/pnas.1720945115;
RA Guo J., Tang H.W., Li J., Perrimon N., Yan D.;
RT "Xio is a component of the Drosophila sex determination pathway and RNA N6-
RT methyladenosine-methyladenosine methyltransferase complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:3674-3679(2018).
CC -!- FUNCTION: Catalytic component of the WMM complex, a complex that
CC mediates N6-methyladenosine (m6A) methylation of mRNAs, a modification
CC that plays a role in the efficiency of mRNA splicing and is required
CC for sex determination (PubMed:27919077, PubMed:27919081,
CC PubMed:28675155). In the heterodimer formed with Mettl14, constitutes
CC the catalytic core (By similarity). Required for sex determination and
CC dosage compensation via Sxl alternative splicing: m6A methylation acts
CC as a key regulator of Sxl pre-mRNA and promotes female-specific
CC alternative splicing of Sxl, which determines female physiognomy
CC (PubMed:27919077, PubMed:27919081, PubMed:28675155). M6A methylation is
CC also required for neuronal functions (PubMed:27919077). During
CC oogenesis, required for egg chamber development probably as part of the
CC N/Notch signaling (PubMed:21873203). {ECO:0000250|UniProtKB:Q86U44,
CC ECO:0000269|PubMed:21873203, ECO:0000269|PubMed:27919077,
CC ECO:0000269|PubMed:27919081, ECO:0000269|PubMed:28675155}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an adenosine in mRNA + S-adenosyl-L-methionine = an N(6)-
CC methyladenosine in mRNA + H(+) + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:55584, Rhea:RHEA-COMP:12414, Rhea:RHEA-COMP:12417,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=2.1.1.348;
CC Evidence={ECO:0000250|UniProtKB:Q86U44};
CC -!- SUBUNIT: Component of the WMM complex, a N6-methyltransferase complex
CC composed of a catalytic subcomplex, named MAC, and of an associated
CC subcomplex, named MACOM (PubMed:29535189, PubMed:28675155,
CC PubMed:29555755). The MAC subcomplex is composed of Ime4/Mettl3 and
CC Mettl14 (PubMed:29535189, PubMed:28675155, PubMed:29555755). The MACOM
CC subcomplex is composed of fl(2)d, Flacc/Xio, Hakai, vir, and, in some
CC cases of nito (PubMed:29535189, PubMed:29555755).
CC {ECO:0000269|PubMed:28675155, ECO:0000269|PubMed:29535189,
CC ECO:0000269|PubMed:29555755}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21873203,
CC ECO:0000269|PubMed:27919077, ECO:0000269|PubMed:27919081,
CC ECO:0000269|PubMed:28675155}.
CC -!- TISSUE SPECIFICITY: Expressed in testes (PubMed:21873203). In the
CC ovaries, detected in germaria, prefollicle, follicle and polar cells
CC (at protein levels) (PubMed:21873203). Detected in the ooplasm and in
CC the cells of the 16-cell cyst of early stages (at protein levels)
CC (PubMed:21873203). {ECO:0000269|PubMed:21873203}.
CC -!- DEVELOPMENTAL STAGE: Ubiquitously expressed in early embryonic stages
CC with enrichment in the neuroectoderm at later stages.
CC {ECO:0000269|PubMed:27919077}.
CC -!- DOMAIN: Gate loop 1 and gate loop 2 regions are adjacent to the S-
CC adenosyl-L-homocysteine-binding site and display large conformational
CC changes upon ligand-binding. They may play an important role in
CC adenosine recognition. The interface loop contributes to the
CC heterodimer interaction. {ECO:0000250|UniProtKB:Q86U44}.
CC -!- DISRUPTION PHENOTYPE: Flies have a reduced lifespan and exhibit
CC multiple behavioral defects: flight and locomotion are severely
CC affected and they spend more time grooming (PubMed:27919077,
CC PubMed:27919081, PubMed:28675155). They also display a mild held-out
CC wing appearance resulting from failure to fold their wings together
CC over the dorsal surface of the thorax and abdomen (PubMed:27919077,
CC PubMed:28675155). RNAi-mediated knockdown results in semi lethality and
CC reduced fertility due to the presence of compound egg chambers with
CC supernumerary nurse cells in the ovaries (PubMed:21873203).
CC {ECO:0000269|PubMed:21873203, ECO:0000269|PubMed:27919077,
CC ECO:0000269|PubMed:27919081, ECO:0000269|PubMed:28675155}.
CC -!- SIMILARITY: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE-
CC ProRule:PRU00489}.
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DR EMBL; AE014297; AAF56221.1; -; Genomic_DNA.
DR EMBL; AY113286; AAM29291.1; -; mRNA.
DR RefSeq; NP_651204.1; NM_142947.4.
DR AlphaFoldDB; Q9VCE6; -.
DR SMR; Q9VCE6; -.
DR BioGRID; 67779; 24.
DR DIP; DIP-17384N; -.
DR IntAct; Q9VCE6; 4.
DR STRING; 7227.FBpp0083917; -.
DR PaxDb; Q9VCE6; -.
DR PRIDE; Q9VCE6; -.
DR DNASU; 42844; -.
DR EnsemblMetazoa; FBtr0084532; FBpp0083917; FBgn0039139.
DR GeneID; 42844; -.
DR KEGG; dme:Dmel_CG5933; -.
DR CTD; 56339; -.
DR FlyBase; FBgn0039139; Mettl3.
DR VEuPathDB; VectorBase:FBgn0039139; -.
DR eggNOG; KOG2098; Eukaryota.
DR GeneTree; ENSGT00550000075058; -.
DR HOGENOM; CLU_018702_4_0_1; -.
DR InParanoid; Q9VCE6; -.
DR OMA; NCMSPAA; -.
DR OrthoDB; 788192at2759; -.
DR PhylomeDB; Q9VCE6; -.
DR Reactome; R-DME-72203; Processing of Capped Intron-Containing Pre-mRNA.
DR BioGRID-ORCS; 42844; 0 hits in 1 CRISPR screen.
DR GenomeRNAi; 42844; -.
DR PRO; PR:Q9VCE6; -.
DR Proteomes; UP000000803; Chromosome 3R.
DR Bgee; FBgn0039139; Expressed in eye disc (Drosophila) and 26 other tissues.
DR Genevisible; Q9VCE6; DM.
DR GO; GO:0005634; C:nucleus; IDA:FlyBase.
DR GO; GO:0036396; C:RNA N6-methyladenosine methyltransferase complex; IDA:UniProtKB.
DR GO; GO:0008168; F:methyltransferase activity; IBA:GO_Central.
DR GO; GO:0016422; F:mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity; IEA:InterPro.
DR GO; GO:0001734; F:mRNA (N6-adenosine)-methyltransferase activity; IMP:FlyBase.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0007549; P:dosage compensation; IMP:FlyBase.
DR GO; GO:0030237; P:female sex determination; IMP:FlyBase.
DR GO; GO:0030708; P:germarium-derived female germ-line cyst encapsulation; IMP:FlyBase.
DR GO; GO:0080009; P:mRNA methylation; IMP:FlyBase.
DR GO; GO:0000398; P:mRNA splicing, via spliceosome; IBA:GO_Central.
DR GO; GO:0030707; P:ovarian follicle cell development; IMP:FlyBase.
DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; IDA:FlyBase.
DR GO; GO:0001510; P:RNA methylation; ISS:UniProtKB.
DR GO; GO:0007530; P:sex determination; IMP:FlyBase.
DR GO; GO:0007548; P:sex differentiation; IEA:UniProtKB-KW.
DR InterPro; IPR025848; MT-A70.
DR InterPro; IPR007757; MT-A70-like.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR Pfam; PF05063; MT-A70; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51143; MT_A70; 1.
PE 1: Evidence at protein level;
KW Differentiation; Methyltransferase; mRNA processing; mRNA splicing;
KW Nucleus; Reference proteome; RNA-binding; S-adenosyl-L-methionine;
KW Sexual differentiation; Transferase.
FT CHAIN 1..608
FT /note="N6-adenosine-methyltransferase MT-A70-like protein"
FT /id="PRO_0000207633"
FT REGION 250..272
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 414..428
FT /note="Gate loop 1"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 480..497
FT /note="Interphase loop"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 483..496
FT /note="Positively charged region required for RNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 525..533
FT /note="Gate loop 2"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT COMPBIAS 250..267
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 395..396
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 413
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 531
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 554..557
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 567..568
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT SITE 456
FT /note="Interaction with Mettl14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT SITE 459
FT /note="Interaction with Mettl14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MUTAGEN 413
FT /note="D->A: Severe lethality; when associated with A-416."
FT /evidence="ECO:0000269|PubMed:21873203"
FT MUTAGEN 416
FT /note="W->A: Severe lethality; when associated with A-413."
FT /evidence="ECO:0000269|PubMed:21873203"
SQ SEQUENCE 608 AA; 68101 MW; 00A2E06082E7FD2F CRC64;
MADAWDIKSL KTKRNTLREK LEKRKKERIE ILSDIQEDLT NPKKELVEAD LEVQKEVLQA
LSSCSLALPI VSTQVVEKIA GSSLEMVNFI LGKLANQGAI VIRNVTIGTE AGCEIISVQP
KELKEILEDT NDTCQQKEEE AKRKLEVDDV DQPQEKTIKL ESTVARKEST SLDAPDDIMM
LLSMPSTREK QSKQVGEEIL ELLTKPTAKE RSVAEKFKSH GGAQVMEFCS HGTKVECLKA
QQATAEMAAK KKQERRDEKE LRPDVDAGEN VTGKVPKTES AAEDGEIIAE VINNCEAESQ
ESTDGSDTCS SETTDKCTKL HFKKIIQAHT DESLGDCSFL NTCFHMATCK YVHYEVDTLP
HINTNKPTDV KTKLSLKRSV DSSCTLYPPQ WIQCDLRFLD MTVLGKFAVV MADPPWDIHM
ELPYGTMSDD EMRALGVPAL QDDGLIFLWV TGRAMELGRD CLKLWGYERV DELIWVKTNQ
LQRIIRTGRT GHWLNHGKEH CLVGMKGNPT NLNRGLDCDV IVAEVRATSH KPDEIYGIIE
RLSPGTRKIE LFGRPHNIQP NWITLGNQLD GIRLVDPELI TQFQKRYPDG NCMSPASANA
ASINGIQK
