MTA70_DANRE
ID MTA70_DANRE Reviewed; 584 AA.
AC F1R777; A8KBZ7; Q6NX96;
DT 19-MAR-2014, integrated into UniProtKB/Swiss-Prot.
DT 03-MAY-2011, sequence version 1.
DT 03-AUG-2022, entry version 76.
DE RecName: Full=N6-adenosine-methyltransferase subunit METTL3;
DE EC=2.1.1.348 {ECO:0000250|UniProtKB:Q86U44, ECO:0000250|UniProtKB:Q8C3P7};
DE AltName: Full=N6-adenosine-methyltransferase 70 kDa subunit;
DE Short=MT-A70;
GN Name=mettl3 {ECO:0000303|PubMed:28869969};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney, and Ovary;
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP DEVELOPMENTAL STAGE.
RX PubMed=24407421; DOI=10.1038/cr.2014.3;
RA Ping X.L., Sun B.F., Wang L., Xiao W., Yang X., Wang W.J., Adhikari S.,
RA Shi Y., Lv Y., Chen Y.S., Zhao X., Li A., Yang Y., Dahal U., Lou X.M.,
RA Liu X., Huang J., Yuan W.P., Zhu X.F., Cheng T., Zhao Y.L., Wang X.,
RA Danielsen J.M., Liu F., Yang Y.G.;
RT "Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine
RT methyltransferase.";
RL Cell Res. 24:177-189(2014).
RN [4]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=28869969; DOI=10.1038/nature23883;
RA Zhang C., Chen Y., Sun B., Wang L., Yang Y., Ma D., Lv J., Heng J.,
RA Ding Y., Xue Y., Lu X., Xiao W., Yang Y.G., Liu F.;
RT "m(6)A modulates haematopoietic stem and progenitor cell specification.";
RL Nature 549:273-276(2017).
CC -!- FUNCTION: The METTL3-METTL14 heterodimer forms a N6-methyltransferase
CC complex that methylates adenosine residues at the N(6) position of some
CC RNAs and regulates various processes such as the circadian clock,
CC differentiation of embryonic and hematopoietic stem cells, cortical
CC neurogenesis, response to DNA damage, differentiation of T-cells and
CC primary miRNA processing (PubMed:28869969). In the heterodimer formed
CC with mettl14, mettl3 constitutes the catalytic core (By similarity).
CC N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3'
CC consensus sites of some mRNAs, plays a role in mRNA stability,
CC processing and translation efficiency (By similarity). M6A is also
CC involved in hematopoietic stem cells specification: m6A methylation and
CC subsequent destabilization of mRNAs, such as notch1a, leads to
CC decreased Notch signaling, promoting endothelial to hematopoietic
CC transition (PubMed:28869969). M6A also takes place in other RNA
CC molecules, such as primary miRNA (pri-miRNAs) (By similarity). Mediates
CC methylation of pri-miRNAs (By similarity).
CC {ECO:0000250|UniProtKB:Q86U44, ECO:0000250|UniProtKB:Q8C3P7,
CC ECO:0000269|PubMed:28869969}.
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 ECO:0000250|UniProtKB:Q8C3P7};
CC -!- SUBUNIT: Heterodimer; heterodimerizes with mettl14 to form an
CC antiparallel heterodimer that constitutes an active methyltransferase.
CC Component of the WMM complex, a N6-methyltransferase complex composed
CC of a catalytic subcomplex, named MAC, and of an associated subcomplex,
CC named MACOM. The MAC subcomplex is composed of mettl3 and mettl14.
CC {ECO:0000250|UniProtKB:Q86U44}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q86U44}. Nucleus
CC speckle {ECO:0000250|UniProtKB:Q86U44}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q86U44}. Note=Colocalizes with speckles in
CC interphase nuclei. Suggesting that it may be associated with nuclear
CC pre-mRNA splicing components. {ECO:0000250|UniProtKB:Q86U44}.
CC -!- TISSUE SPECIFICITY: Expressed in the hemato-vascular system: enriched
CC in sorted endothelial cells and haemogenic endothelium
CC (PubMed:28869969). {ECO:0000269|PubMed:28869969}.
CC -!- DEVELOPMENTAL STAGE: Maternally expressed from the 4-cell stage and
CC ubiquitously expressed through early embryogenesis, with enriched
CC expression in the brain region at 36 hpf (hours post fertilization)
CC (PubMed:24407421). {ECO:0000269|PubMed:24407421}.
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: Lethality 10 days post-fertilization (dpf) due to
CC severe hematopoietic defects (PubMed:28869969). Levels of N6-
CC methyladenosine (m6A)-containing mRNAs are significantly decreased and
CC emergence of hematopoietic stem cells is blocked (PubMed:28869969).
CC {ECO:0000269|PubMed:28869969}.
CC -!- SIMILARITY: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE-
CC ProRule:PRU00489}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; BX005336; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC067182; AAH67182.1; -; mRNA.
DR EMBL; BC154303; AAI54304.1; -; mRNA.
DR RefSeq; NP_997945.1; NM_212780.1.
DR AlphaFoldDB; F1R777; -.
DR SMR; F1R777; -.
DR STRING; 7955.ENSDARP00000022188; -.
DR PaxDb; F1R777; -.
DR PRIDE; F1R777; -.
DR Ensembl; ENSDART00000019699; ENSDARP00000022188; ENSDARG00000012827.
DR GeneID; 100004398; -.
DR KEGG; dre:100004398; -.
DR CTD; 56339; -.
DR ZFIN; ZDB-GENE-030131-9498; mettl3.
DR eggNOG; KOG2098; Eukaryota.
DR GeneTree; ENSGT00550000075058; -.
DR HOGENOM; CLU_018702_4_0_1; -.
DR InParanoid; F1R777; -.
DR OMA; MKGNPRI; -.
DR OrthoDB; 788192at2759; -.
DR PhylomeDB; F1R777; -.
DR TreeFam; TF323854; -.
DR BRENDA; 2.1.1.348; 928.
DR Reactome; R-DRE-72203; Processing of Capped Intron-Containing Pre-mRNA.
DR PRO; PR:F1R777; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 7.
DR Bgee; ENSDARG00000012827; Expressed in mature ovarian follicle and 27 other tissues.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0036396; C:RNA N6-methyladenosine methyltransferase complex; ISS:UniProtKB.
DR GO; GO:0008168; F:methyltransferase activity; IBA:GO_Central.
DR GO; GO:0016422; F:mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity; IMP:ZFIN.
DR GO; GO:0001734; F:mRNA (N6-adenosine)-methyltransferase activity; IMP:ZFIN.
DR GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0008173; F:RNA methyltransferase activity; ISS:UniProtKB.
DR GO; GO:1904047; F:S-adenosyl-L-methionine binding; ISS:UniProtKB.
DR GO; GO:0006382; P:adenosine to inosine editing; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0034644; P:cellular response to UV; ISS:UniProtKB.
DR GO; GO:0098508; P:endothelial to hematopoietic transition; IMP:UniProtKB.
DR GO; GO:0030317; P:flagellated sperm motility; IMP:ZFIN.
DR GO; GO:0021861; P:forebrain radial glial cell differentiation; ISS:UniProtKB.
DR GO; GO:0042063; P:gliogenesis; ISS:UniProtKB.
DR GO; GO:0071425; P:hematopoietic stem cell proliferation; IMP:ZFIN.
DR GO; GO:0006402; P:mRNA catabolic process; ISS:UniProtKB.
DR GO; GO:0061157; P:mRNA destabilization; ISS:UniProtKB.
DR GO; GO:0080009; P:mRNA methylation; IMP:UniProtKB.
DR GO; GO:0000398; P:mRNA splicing, via spliceosome; ISS:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IMP:UniProtKB.
DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0060853; P:Notch signaling pathway involved in arterial endothelial cell fate commitment; IMP:ZFIN.
DR GO; GO:0001556; P:oocyte maturation; IMP:ZFIN.
DR GO; GO:0048477; P:oogenesis; ISS:UniProtKB.
DR GO; GO:1903679; P:positive regulation of cap-independent translational initiation; ISS:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; ISS:UniProtKB.
DR GO; GO:0031053; P:primary miRNA processing; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IGI:ZFIN.
DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; IMP:UniProtKB.
DR GO; GO:0051445; P:regulation of meiotic cell cycle; ISS:UniProtKB.
DR GO; GO:0090365; P:regulation of mRNA modification; IMP:ZFIN.
DR GO; GO:0045580; P:regulation of T cell differentiation; ISS:UniProtKB.
DR GO; GO:0007530; P:sex determination; IMP:ZFIN.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR GO; GO:0019827; P:stem cell population maintenance; ISS:UniProtKB.
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.
DR PROSITE; PS51563; SAM_MTA70L_1; 1.
PE 2: Evidence at transcript level;
KW Cytoplasm; Differentiation; DNA damage; Methyltransferase; Nucleus;
KW Reference proteome; RNA-binding; S-adenosyl-L-methionine; Spermatogenesis;
KW Transferase.
FT CHAIN 1..584
FT /note="N6-adenosine-methyltransferase subunit METTL3"
FT /id="PRO_0000425902"
FT REGION 1..65
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 162..221
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 400..414
FT /note="Gate loop 1"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 454..458
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 466..483
FT /note="Interphase loop"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 468..484
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 469..482
FT /note="Positively charged region required for RNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 511..519
FT /note="Gate loop 2"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOTIF 213..220
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT COMPBIAS 9..31
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 34..53
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 185..206
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 381..382
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 399
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 517
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 540..543
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 553..554
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT SITE 442
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT SITE 445
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT CONFLICT 173
FT /note="L -> P (in Ref. 2; AAH67182/AAI54304)"
FT /evidence="ECO:0000305"
FT CONFLICT 176
FT /note="S -> A (in Ref. 2; AAI54304)"
FT /evidence="ECO:0000305"
FT CONFLICT 356
FT /note="A -> T (in Ref. 2; AAI54304)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 584 AA; 64627 MW; F465178A0558F658 CRC64;
MSDTWSHIQA HKKQLDSLRE RLQRRRKDPT QLGTEVGSVE SGSARSDSPG PAIQSPPQVE
VEHPPDPELE KRLLGYLSEL SLSLPTDSLT ITNQLNTSES PVSHSCIQSL LLKFSAQELI
EVRQPSITSS SSSTLVTSVD HTKLWAMIGS AGQSQRTAVK RKADDITHQK RALGSSPSIQ
APPSPPRKSS VSLATASISQ LTASSGGGGG GADKKGRSNK VQASHLDMEI ESLLSQQSTK
EQQSKKVSQE ILELLNTSSA KEQSIVEKFR SRGRAQVQEF CDYGTKEECV QSGDTPQPCT
KLHFRRIINK HTDESLGDCS FLNTCFHMDT CKYVHYEIDS PPEAEGDALG PQAGAAELGL
HSTVGDSNVG KLFPSQWICC DIRYLDVSIL GKFAVVMADP PWDIHMELPY GTLTDDEMRK
LNIPILQDDG FLFLWVTGRA MELGRECLSL WGYDRVDEII WVKTNQLQRI IRTGRTGHWL
NHGKEHCLVG VKGNPQGFNR GLDCDVIVAE VRSTSHKPDE IYGMIERLSP GTRKIELFGR
PHNVQPNWIT LGNQLDGIHL LDPEVVARFK KRYPDGVISK PKNM
