ID MTA70_HUMAN Reviewed; 580 AA.
AC Q86U44; O14736; Q86V05; Q9HB32;
DT 25-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT 25-JUL-2003, sequence version 2.
DT 02-OCT-2024, entry version 174.
DE RecName: Full=N6-adenosine-methyltransferase catalytic subunit {ECO:0000305};
DE EC=2.1.1.348 {ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:9409616};
DE AltName: Full=Methyltransferase-like protein 3 {ECO:0000305};
DE Short=hMETTL3 {ECO:0000303|PubMed:27373337};
DE AltName: Full=N6-adenosine-methyltransferase 70 kDa subunit;
DE Short=MT-A70;
GN Name=METTL3 {ECO:0000312|HGNC:HGNC:17563}; Synonyms=MTA70;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), PROTEIN SEQUENCE OF 48-56;
RP 134-149 AND 509-522, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP AND CATALYTIC ACTIVITY.
RX PubMed=9409616;
RA Bokar J.A., Shambaugh M.E., Polayes D., Matera A.G., Rottman F.M.;
RT "Purification and cDNA cloning of the AdoMet-binding subunit of the human
RT mRNA (N6-adenosine)-methyltransferase.";
RL RNA 3:1233-1247(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Placenta;
RA Li W.B., Gruber C., Jessee J., Polayes D.;
RT "Full-length cDNA libraries and normalization.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43; SER-219 AND SER-243, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP FUNCTION.
RX PubMed=22575960; DOI=10.1038/nature11112;
RA Dominissini D., Moshitch-Moshkovitz S., Schwartz S., Salmon-Divon M.,
RA Ungar L., Osenberg S., Cesarkas K., Jacob-Hirsch J., Amariglio N.,
RA Kupiec M., Sorek R., Rechavi G.;
RT "Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.";
RL Nature 485:201-206(2012).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43; SER-219 AND THR-348, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [14]
RP IDENTIFICATION IN THE WMM COMPLEX.
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 [15]
RP IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=24981863; DOI=10.1016/j.celrep.2014.05.048;
RA Schwartz S., Mumbach M.R., Jovanovic M., Wang T., Maciag K., Bushkin G.G.,
RA Mertins P., Ter-Ovanesyan D., Habib N., Cacchiarelli D., Sanjana N.E.,
RA Freinkman E., Pacold M.E., Satija R., Mikkelsen T.S., Hacohen N., Zhang F.,
RA Carr S.A., Lander E.S., Regev A.;
RT "Perturbation of m6A writers reveals two distinct classes of mRNA
RT methylation at internal and 5' sites.";
RL Cell Rep. 8:284-296(2014).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [17]
RP FUNCTION.
RX PubMed=24284625; DOI=10.1038/nature12730;
RA Wang X., Lu Z., Gomez A., Hon G.C., Yue Y., Han D., Fu Y., Parisien M.,
RA Dai Q., Jia G., Ren B., Pan T., He C.;
RT "N-methyladenosine-dependent regulation of messenger RNA stability.";
RL Nature 505:117-120(2014).
RN [18]
RP FUNCTION.
RX PubMed=25719671; DOI=10.1038/nature14234;
RA Liu N., Dai Q., Zheng G., He C., Parisien M., Pan T.;
RT "N(6)-methyladenosine-dependent RNA structural switches regulate RNA-
RT protein interactions.";
RL Nature 518:560-564(2015).
RN [19]
RP FUNCTION, AND MUTAGENESIS OF 395-ASP--TRP-398.
RX PubMed=25799998; DOI=10.1038/nature14281;
RA Alarcon C.R., Lee H., Goodarzi H., Halberg N., Tavazoie S.F.;
RT "N6-methyladenosine marks primary microRNAs for processing.";
RL Nature 519:482-485(2015).
RN [20]
RP FUNCTION.
RX PubMed=26321680; DOI=10.1016/j.cell.2015.08.011;
RA Alarcon C.R., Goodarzi H., Lee H., Liu X., Tavazoie S., Tavazoie S.F.;
RT "HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing
RT events.";
RL Cell 162:1299-1308(2015).
RN [21]
RP FUNCTION.
RX PubMed=26593424; DOI=10.1016/j.cell.2015.10.012;
RA Meyer K.D., Patil D.P., Zhou J., Zinoviev A., Skabkin M.A., Elemento O.,
RA Pestova T.V., Qian S.B., Jaffrey S.R.;
RT "5' UTR m(6)A promotes cap-independent translation.";
RL Cell 163:999-1010(2015).
RN [22]
RP SUBCELLULAR LOCATION.
RX PubMed=26458103; DOI=10.1038/nature15377;
RA Zhou J., Wan J., Gao X., Zhang X., Jaffrey S.R., Qian S.B.;
RT "Dynamic m(6)A mRNA methylation directs translational control of heat shock
RT response.";
RL Nature 526:591-594(2015).
RN [23]
RP FUNCTION, SUBCELLULAR LOCATION, INDUCTION, INTERACTION WITH NCBP1; EIF4E
RP AND EIF3B, AND MUTAGENESIS OF 395-ASP--TRP-398.
RX PubMed=27117702; DOI=10.1016/j.molcel.2016.03.021;
RA Lin S., Choe J., Du P., Triboulet R., Gregory R.I.;
RT "The m(6)A methyltransferase METTL3 promotes translation in human cancer
RT cells.";
RL Mol. Cell 62:335-345(2016).
RN [24]
RP FUNCTION, AND IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=27602518; DOI=10.1038/nature19342;
RA Patil D.P., Chen C.K., Pickering B.F., Chow A., Jackson C., Guttman M.,
RA Jaffrey S.R.;
RT "m(6)A RNA methylation promotes XIST-mediated transcriptional repression.";
RL Nature 537:369-373(2016).
RN [25]
RP FUNCTION.
RX PubMed=28637692; DOI=10.1101/gad.301036.117;
RA Ke S., Pandya-Jones A., Saito Y., Fak J.J., Vaagboe C.B., Geula S.,
RA Hanna J.H., Black D.L., Darnell J.E. Jr., Darnell R.B.;
RT "m(6)A mRNA modifications are deposited in nascent pre-mRNA and are not
RT required for splicing but do specify cytoplasmic turnover.";
RL Genes Dev. 31:990-1006(2017).
RN [26]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 395-ASP--TRP-398.
RX PubMed=28297716; DOI=10.1038/nature21671;
RA Xiang Y., Laurent B., Hsu C.H., Nachtergaele S., Lu Z., Sheng W., Xu C.,
RA Chen H., Ouyang J., Wang S., Ling D., Hsu P.H., Zou L., Jambhekar A.,
RA He C., Shi Y.;
RT "RNA m(6)A methylation regulates the ultraviolet-induced DNA damage
RT response.";
RL Nature 543:573-576(2017).
RN [27]
RP ERRATUM OF PUBMED:28297716.
RX PubMed=29186122; DOI=10.1038/nature24007;
RA Xiang Y., Laurent B., Hsu C.H., Nachtergaele S., Lu Z., Sheng W., Xu C.,
RA Chen H., Ouyang J., Wang S., Ling D., Hsu P.H., Zou L., Jambhekar A.,
RA He C., Shi Y.;
RL Nature 552:430-430(2017).
RN [28]
RP IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=29507755; DOI=10.1038/s41421-018-0019-0;
RA Yue Y., Liu J., Cui X., Cao J., Luo G., Zhang Z., Cheng T., Gao M., Shu X.,
RA Ma H., Wang F., Wang X., Shen B., Wang Y., Feng X., He C., Liu J.;
RT "VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop
RT codon and associates with alternative polyadenylation.";
RL Cell Discov. 4:10-10(2018).
RN [29]
RP FUNCTION.
RX PubMed=30428350; DOI=10.1016/j.celrep.2018.10.068;
RA Zhong X., Yu J., Frazier K., Weng X., Li Y., Cham C.M., Dolan K., Zhu X.,
RA Hubert N., Tao Y., Lin F., Martinez-Guryn K., Huang Y., Wang T., Liu J.,
RA He C., Chang E.B., Leone V.;
RT "Circadian clock regulation of hepatic lipid metabolism by modulation of
RT m6A mRNA methylation.";
RL Cell Rep. 25:1816-1828(2018).
RN [30]
RP FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP IDENTIFICATION IN THE WMM COMPLEX, SUMOYLATION AT LYS-177; LYS-211; LYS-212
RP AND LYS-215, AND MUTAGENESIS OF LYS-177 AND 211-LYS--LYS-215.
RX PubMed=29506078; DOI=10.1093/nar/gky156;
RA Du Y., Hou G., Zhang H., Dou J., He J., Guo Y., Li L., Chen R., Wang Y.,
RA Deng R., Huang J., Jiang B., Xu M., Cheng J., Chen G.Q., Zhao X., Yu J.;
RT "SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its
RT function.";
RL Nucleic Acids Res. 46:5195-5208(2018).
RN [31]
RP FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN THE WMM COMPLEX,
RP PHOSPHORYLATION AT SER-2; SER-43; SER-48; SER-50; SER-219; SER-243; THR-348
RP AND SER-350, AND MUTAGENESIS OF SER-2; SER-43; SER-48; SER-50; SER-219;
RP SER-243; 211-LYS--LYS-215 AND 348-THR--SER-350.
RX PubMed=29348140; DOI=10.1261/rna.064063.117;
RA Schoeller E., Weichmann F., Treiber T., Ringle S., Treiber N., Flatley A.,
RA Feederle R., Bruckmann A., Meister G.;
RT "Interactions, localization, and phosphorylation of the m6A generating
RT METTL3-METTL14-WTAP complex.";
RL RNA 24:499-512(2018).
RN [32]
RP FUNCTION.
RX PubMed=30559377; DOI=10.1038/s41590-018-0275-z;
RA Winkler R., Gillis E., Lasman L., Safra M., Geula S., Soyris C.,
RA Nachshon A., Tai-Schmiedel J., Friedman N., Le-Trilling V.T.K.,
RA Trilling M., Mandelboim M., Hanna J.H., Schwartz S., Stern-Ginossar N.;
RT "m6A modification controls the innate immune response to infection by
RT targeting type I interferons.";
RL Nat. Immunol. 20:173-182(2019).
RN [33]
RP FUNCTION.
RX PubMed=33961823; DOI=10.1016/j.celrep.2021.109091;
RA Li N., Hui H., Bray B., Gonzalez G.M., Zeller M., Anderson K.G., Knight R.,
RA Smith D., Wang Y., Carlin A.F., Rana T.M.;
RT "METTL3 regulates viral m6A RNA modification and host cell innate immune
RT responses during SARS-CoV-2 infection.";
RL Cell Rep. 35:109091-109091(2021).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 354-580 IN COMPLEX WITH METTL14
RP AND S-ADENOSYL-L-METHIONINE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND
RP MUTAGENESIS OF ASP-395; TYR-406; ASN-549 AND GLN-550.
RX PubMed=27627798; DOI=10.7554/elife.18434;
RA Sledz P., Jinek M.;
RT "Structural insights into the molecular mechanism of the m(6)A writer
RT complex.";
RL Elife 5:E18434-E18434(2016).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 357-580 IN COMPLEX WITH METTL14
RP AND S-ADENOSYL-L-METHIONINE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT,
RP MUTAGENESIS OF CYS-294; CYS-326; ASP-395; TRP-475 AND ASN-477, VARIANT
RP CYS-406, AND CHARACTERIZATION OF VARIANT CYS-406.
RX PubMed=27373337; DOI=10.1016/j.molcel.2016.05.041;
RA Wang P., Doxtader K.A., Nam Y.;
RT "Structural basis for cooperative function of Mettl3 and Mettl14
RT methyltransferases.";
RL Mol. Cell 63:306-317(2016).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (1.61 ANGSTROMS) OF 369-580 IN COMPLEX WITH METTL14
RP AND S-ADENOSYL-L-METHIONINE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, DOMAIN,
RP AND MUTAGENESIS OF ASP-377; ASP-395; 462-GLN--GLY-479; GLU-532; ARG-536;
RP HIS-538; ASN-539; ASN-549 AND GLN-550.
RX PubMed=27281194; DOI=10.1038/nature18298;
RA Wang X., Feng J., Xue Y., Guan Z., Zhang D., Liu Z., Gong Z., Wang Q.,
RA Huang J., Tang C., Zou T., Yin P.;
RT "Structural basis of N(6)-adenosine methylation by the METTL3-METTL14
RT complex.";
RL Nature 534:575-578(2016).
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:22575960, PubMed:24284625,
CC PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424,
CC PubMed:27281194, PubMed:27373337, PubMed:27627798, PubMed:28297716,
CC PubMed:29348140, PubMed:29506078, PubMed:30428350, PubMed:9409616). In
CC the heterodimer formed with METTL14, METTL3 constitutes the catalytic
CC core (PubMed:27281194, PubMed:27373337, PubMed:27627798). N6-
CC methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus
CC sites of some mRNAs, plays a role in mRNA stability, processing,
CC translation efficiency and editing (PubMed:22575960, PubMed:24284625,
CC PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424,
CC PubMed:28297716, PubMed:9409616). M6A acts as a key regulator of mRNA
CC stability: methylation is completed upon the release of mRNA into the
CC nucleoplasm and promotes mRNA destabilization and degradation
CC (PubMed:28637692). In embryonic stem cells (ESCs), m6A methylation of
CC mRNAs encoding key naive pluripotency-promoting transcripts results in
CC transcript destabilization, promoting differentiation of ESCs (By
CC similarity). M6A regulates the length of the circadian clock: acts as
CC an early pace-setter in the circadian loop by putting mRNA production
CC on a fast-track for facilitating nuclear processing, thereby providing
CC an early point of control in setting the dynamics of the feedback loop
CC (By similarity). M6A also regulates circadian regulation of hepatic
CC lipid metabolism (PubMed:30428350). M6A regulates spermatogonial
CC differentiation and meiosis and is essential for male fertility and
CC spermatogenesis (By similarity). Also required for oogenesis (By
CC similarity). Involved in the response to DNA damage: in response to
CC ultraviolet irradiation, METTL3 rapidly catalyzes the formation of m6A
CC on poly(A) transcripts at DNA damage sites, leading to the recruitment
CC of POLK to DNA damage sites (PubMed:28297716). M6A is also required for
CC T-cell homeostasis and differentiation: m6A methylation of transcripts
CC of SOCS family members (SOCS1, SOCS3 and CISH) in naive T-cells
CC promotes mRNA destabilization and degradation, promoting T-cell
CC differentiation (By similarity). Inhibits the type I interferon
CC response by mediating m6A methylation of IFNB (PubMed:30559377). M6A
CC also takes place in other RNA molecules, such as primary miRNA (pri-
CC miRNAs) (PubMed:25799998). Mediates m6A methylation of Xist RNA,
CC thereby participating in random X inactivation: m6A methylation of Xist
CC leads to target YTHDC1 reader on Xist and promote transcription
CC repression activity of Xist (PubMed:27602518). M6A also regulates
CC cortical neurogenesis: m6A methylation of transcripts related to
CC transcription factors, neural stem cells, the cell cycle and neuronal
CC differentiation during brain development promotes their destabilization
CC and decay, promoting differentiation of radial glial cells (By
CC similarity). METTL3 mediates methylation of pri-miRNAs, marking them
CC for recognition and processing by DGCR8 (PubMed:25799998). Acts as a
CC positive regulator of mRNA translation independently of the
CC methyltransferase activity: promotes translation by interacting with
CC the translation initiation machinery in the cytoplasm
CC (PubMed:27117702). Its overexpression in a number of cancer cells
CC suggests that it may participate in cancer cell proliferation by
CC promoting mRNA translation (PubMed:27117702). During human coronavirus
CC SARS-CoV-2 infection, adds m6A modifications in SARS-CoV-2 RNA leading
CC to decreased RIGI binding and subsequently dampening the sensing and
CC activation of innate immune responses (PubMed:33961823).
CC {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:22575960,
CC ECO:0000269|PubMed:24284625, ECO:0000269|PubMed:25719671,
CC ECO:0000269|PubMed:25799998, ECO:0000269|PubMed:26321680,
CC ECO:0000269|PubMed:26593424, ECO:0000269|PubMed:27117702,
CC ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337,
CC ECO:0000269|PubMed:27602518, ECO:0000269|PubMed:27627798,
CC ECO:0000269|PubMed:28297716, ECO:0000269|PubMed:28637692,
CC ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078,
CC ECO:0000269|PubMed:30428350, ECO:0000269|PubMed:30559377,
CC ECO:0000269|PubMed:33961823, ECO:0000269|PubMed:9409616}.
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:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337,
CC ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:29348140,
CC ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:9409616};
CC -!- ACTIVITY REGULATION: Methyltransferase activity is regulated by miRNAs
CC via a sequence pairing mechanism (By similarity). Methyltransferase
CC activity is inhibited by sumoylation (PubMed:29506078).
CC {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:29506078}.
CC -!- SUBUNIT: Heterodimer; heterodimerizes with METTL14 to form an
CC antiparallel heterodimer that constitutes an active methyltransferase
CC (PubMed:27281194, PubMed:27373337, PubMed:27627798). Component of the
CC WMM complex, a N6-methyltransferase complex composed of a catalytic
CC subcomplex, named MAC, and of an associated subcomplex, named MACOM
CC (PubMed:24407421, PubMed:24981863, PubMed:27602518, PubMed:29348140,
CC PubMed:29506078, PubMed:29507755). The MAC subcomplex is composed of
CC METTL3 and METTL14 (PubMed:24407421, PubMed:24981863, PubMed:27602518,
CC PubMed:29507755). The MACOM subcomplex is composed of WTAP, ZC3H13,
CC CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B)
CC (PubMed:27602518, PubMed:29507755). Interacts with NCBP1/CBP80
CC (PubMed:27117702). Interacts with EIF4E (PubMed:27117702). Interacts
CC with EIF3B (PubMed:27117702). {ECO:0000269|PubMed:24407421,
CC ECO:0000269|PubMed:24981863, ECO:0000269|PubMed:27117702,
CC ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337,
CC ECO:0000269|PubMed:27602518, ECO:0000269|PubMed:27627798,
CC ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078,
CC ECO:0000269|PubMed:29507755}.
CC -!- INTERACTION:
CC Q86U44; Q9HCE5: METTL14; NbExp=21; IntAct=EBI-11105430, EBI-6661081;
CC Q86U44-1; Q9HCE5: METTL14; NbExp=10; IntAct=EBI-16084936, EBI-6661081;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:25719671,
CC ECO:0000269|PubMed:26458103, ECO:0000269|PubMed:27117702,
CC ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078}. Nucleus
CC speckle {ECO:0000269|PubMed:9409616}. Cytoplasm
CC {ECO:0000269|PubMed:27117702}. Note=Colocalizes with speckles in
CC interphase nuclei, suggesting that it may be associated with nuclear
CC pre-mRNA splicing components (PubMed:9409616). In response to
CC ultraviolet irradiation, colocalizes to DNA damage sites however, it
CC probably does not bind DNA but localizes in the vicinity of DNA damage
CC sites (PubMed:28297716). {ECO:0000269|PubMed:28297716,
CC ECO:0000269|PubMed:9409616}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q86U44-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q86U44-2; Sequence=VSP_007864, VSP_007865, VSP_007866;
CC -!- TISSUE SPECIFICITY: Widely expressed at low level. Expressed in spleen,
CC thymus, prostate, testis, ovary, small intestine, colon and peripheral
CC blood leukocytes. {ECO:0000269|PubMed:9409616}.
CC -!- INDUCTION: Overexpressed in a number of cancer tissues, such as lung
CC adenocarcinoma and colon adenocarcinoma (PubMed:27117702).
CC {ECO:0000269|PubMed:27117702}.
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:0000269|PubMed:27281194}.
CC -!- PTM: Sumoylation inhibits the N6-adenosine-methyltransferase activity.
CC Sumoylation does not affect subcellular location or interaction with
CC METTL14. Desumoylated by SENP1. {ECO:0000269|PubMed:29506078}.
CC -!- SIMILARITY: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE-
CC ProRule:PRU00489}.
CC ---------------------------------------------------------------------------
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DR EMBL; AF014837; AAB71850.1; -; Genomic_DNA.
DR EMBL; AF283991; AAG13956.1; -; Genomic_DNA.
DR EMBL; AE000658; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BX247964; CAD62303.1; -; mRNA.
DR EMBL; BC003031; AAH03031.1; -; mRNA.
DR EMBL; BC001650; AAH01650.1; -; mRNA.
DR EMBL; BC052244; AAH52244.1; -; mRNA.
DR CCDS; CCDS32044.1; -. [Q86U44-1]
DR RefSeq; NP_062826.2; NM_019852.4. [Q86U44-1]
DR PDB; 5IL0; X-ray; 1.88 A; A=369-580.
DR PDB; 5IL1; X-ray; 1.71 A; A=369-580.
DR PDB; 5IL2; X-ray; 1.61 A; A=369-580.
DR PDB; 5K7M; X-ray; 1.65 A; A=357-580.
DR PDB; 5K7U; X-ray; 1.70 A; A=357-580.
DR PDB; 5K7W; X-ray; 1.65 A; A=357-580.
DR PDB; 5L6D; X-ray; 1.85 A; A=354-580.
DR PDB; 5L6E; X-ray; 1.90 A; A=354-580.
DR PDB; 5TEY; X-ray; 1.80 A; A=1-580.
DR PDB; 5YZ9; Other; -; A=259-357.
DR PDB; 6TTP; X-ray; 2.00 A; A=1-580.
DR PDB; 6TTT; X-ray; 2.30 A; A=1-580.
DR PDB; 6TTV; X-ray; 2.14 A; A=1-580.
DR PDB; 6TTW; X-ray; 2.20 A; A=1-580.
DR PDB; 6TTX; X-ray; 2.00 A; A=1-580.
DR PDB; 6TU1; X-ray; 2.31 A; A=1-580.
DR PDB; 6Y4G; X-ray; 1.90 A; A=1-580.
DR PDB; 7ACD; X-ray; 2.50 A; A=354-580.
DR PDB; 7NHG; X-ray; 2.50 A; A=354-580.
DR PDB; 7NHH; X-ray; 2.10 A; A=354-580.
DR PDB; 7NHI; X-ray; 1.85 A; A=354-580.
DR PDB; 7NHJ; X-ray; 2.16 A; A=354-580.
DR PDB; 7NHV; X-ray; 1.91 A; A=354-580.
DR PDB; 7NI7; X-ray; 2.50 A; A=354-580.
DR PDB; 7NI8; X-ray; 2.20 A; A=354-580.
DR PDB; 7NI9; X-ray; 2.20 A; A=354-580.
DR PDB; 7NIA; X-ray; 2.30 A; A=354-580.
DR PDB; 7NID; X-ray; 2.30 A; A=354-580.
DR PDB; 7O08; X-ray; 2.00 A; A=354-580.
DR PDB; 7O09; X-ray; 1.80 A; A=354-580.
DR PDB; 7O0L; X-ray; 1.90 A; A=354-580.
DR PDB; 7O0M; X-ray; 2.39 A; A=354-580.
DR PDB; 7O0P; X-ray; 2.70 A; A=354-580.
DR PDB; 7O0Q; X-ray; 2.49 A; A=354-580.
DR PDB; 7O0R; X-ray; 2.30 A; A=354-580.
DR PDB; 7O27; X-ray; 2.40 A; A=354-580.
DR PDB; 7O28; X-ray; 2.47 A; A=354-580.
DR PDB; 7O29; X-ray; 2.75 A; A=354-580.
DR PDB; 7O2E; X-ray; 2.50 A; A=354-580.
DR PDB; 7O2F; X-ray; 2.10 A; A=354-580.
DR PDB; 7O2H; X-ray; 2.50 A; A=354-580.
DR PDB; 7O2I; X-ray; 3.00 A; A=353-580.
DR PDB; 7O2X; X-ray; 2.80 A; A=354-580.
DR PDB; 7OED; X-ray; 2.00 A; A=354-580.
DR PDB; 7OEE; X-ray; 2.70 A; A=354-580.
DR PDB; 7OEF; X-ray; 2.03 A; A=354-580.
DR PDB; 7OEG; X-ray; 2.79 A; A=354-580.
DR PDB; 7OEH; X-ray; 2.01 A; A=354-580.
DR PDB; 7OEI; X-ray; 2.48 A; A=354-580.
DR PDB; 7OEJ; X-ray; 2.30 A; A=354-580.
DR PDB; 7OEK; X-ray; 1.90 A; A=354-580.
DR PDB; 7OEL; X-ray; 1.86 A; A=354-580.
DR PDB; 7OEM; X-ray; 2.20 A; A=354-580.
DR PDB; 7OQL; X-ray; 2.50 A; A=354-580.
DR PDB; 7OQO; X-ray; 3.35 A; A=354-580.
DR PDB; 7OQP; X-ray; 2.00 A; A=354-580.
DR PDB; 7RX6; X-ray; 1.80 A; A=357-580.
DR PDB; 7RX7; X-ray; 1.65 A; A=357-580.
DR PDB; 7RX8; X-ray; 1.85 A; A=357-580.
DR PDB; 8BN8; X-ray; 2.21 A; AAA=363-580.
DR PDB; 8PW8; X-ray; 2.30 A; A=353-580.
DR PDB; 8PW9; X-ray; 2.30 A; A=353-580.
DR PDB; 8PWA; X-ray; 2.10 A; A=353-580.
DR PDB; 8PWB; X-ray; 2.50 A; A=353-580.
DR PDBsum; 5IL0; -.
DR PDBsum; 5IL1; -.
DR PDBsum; 5IL2; -.
DR PDBsum; 5K7M; -.
DR PDBsum; 5K7U; -.
DR PDBsum; 5K7W; -.
DR PDBsum; 5L6D; -.
DR PDBsum; 5L6E; -.
DR PDBsum; 5TEY; -.
DR PDBsum; 5YZ9; -.
DR PDBsum; 6TTP; -.
DR PDBsum; 6TTT; -.
DR PDBsum; 6TTV; -.
DR PDBsum; 6TTW; -.
DR PDBsum; 6TTX; -.
DR PDBsum; 6TU1; -.
DR PDBsum; 6Y4G; -.
DR PDBsum; 7ACD; -.
DR PDBsum; 7NHG; -.
DR PDBsum; 7NHH; -.
DR PDBsum; 7NHI; -.
DR PDBsum; 7NHJ; -.
DR PDBsum; 7NHV; -.
DR PDBsum; 7NI7; -.
DR PDBsum; 7NI8; -.
DR PDBsum; 7NI9; -.
DR PDBsum; 7NIA; -.
DR PDBsum; 7NID; -.
DR PDBsum; 7O08; -.
DR PDBsum; 7O09; -.
DR PDBsum; 7O0L; -.
DR PDBsum; 7O0M; -.
DR PDBsum; 7O0P; -.
DR PDBsum; 7O0Q; -.
DR PDBsum; 7O0R; -.
DR PDBsum; 7O27; -.
DR PDBsum; 7O28; -.
DR PDBsum; 7O29; -.
DR PDBsum; 7O2E; -.
DR PDBsum; 7O2F; -.
DR PDBsum; 7O2H; -.
DR PDBsum; 7O2I; -.
DR PDBsum; 7O2X; -.
DR PDBsum; 7OED; -.
DR PDBsum; 7OEE; -.
DR PDBsum; 7OEF; -.
DR PDBsum; 7OEG; -.
DR PDBsum; 7OEH; -.
DR PDBsum; 7OEI; -.
DR PDBsum; 7OEJ; -.
DR PDBsum; 7OEK; -.
DR PDBsum; 7OEL; -.
DR PDBsum; 7OEM; -.
DR PDBsum; 7OQL; -.
DR PDBsum; 7OQO; -.
DR PDBsum; 7OQP; -.
DR PDBsum; 7RX6; -.
DR PDBsum; 7RX7; -.
DR PDBsum; 7RX8; -.
DR PDBsum; 8BN8; -.
DR PDBsum; 8PW8; -.
DR PDBsum; 8PW9; -.
DR PDBsum; 8PWA; -.
DR PDBsum; 8PWB; -.
DR AlphaFoldDB; Q86U44; -.
DR SMR; Q86U44; -.
DR BioGRID; 121139; 290.
DR ComplexPortal; CPX-1605; WMM N6-adenosine-methyltransferase complex.
DR DIP; DIP-60727N; -.
DR IntAct; Q86U44; 246.
DR MINT; Q86U44; -.
DR STRING; 9606.ENSP00000298717; -.
DR BindingDB; Q86U44; -.
DR ChEMBL; CHEMBL4739695; -.
DR GuidetoPHARMACOLOGY; 3181; -.
DR GlyGen; Q86U44; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q86U44; -.
DR PhosphoSitePlus; Q86U44; -.
DR BioMuta; METTL3; -.
DR DMDM; 33301371; -.
DR jPOST; Q86U44; -.
DR MassIVE; Q86U44; -.
DR PaxDb; 9606-ENSP00000298717; -.
DR PeptideAtlas; Q86U44; -.
DR ProteomicsDB; 69768; -. [Q86U44-1]
DR ProteomicsDB; 69769; -. [Q86U44-2]
DR Pumba; Q86U44; -.
DR Antibodypedia; 53; 233 antibodies from 29 providers.
DR DNASU; 56339; -.
DR Ensembl; ENST00000298717.9; ENSP00000298717.3; ENSG00000165819.12. [Q86U44-1]
DR GeneID; 56339; -.
DR KEGG; hsa:56339; -.
DR MANE-Select; ENST00000298717.9; ENSP00000298717.3; NM_019852.5; NP_062826.2.
DR UCSC; uc001wbc.4; human. [Q86U44-1]
DR AGR; HGNC:17563; -.
DR CTD; 56339; -.
DR DisGeNET; 56339; -.
DR GeneCards; METTL3; -.
DR HGNC; HGNC:17563; METTL3.
DR HPA; ENSG00000165819; Low tissue specificity.
DR MIM; 612472; gene.
DR neXtProt; NX_Q86U44; -.
DR OpenTargets; ENSG00000165819; -.
DR PharmGKB; PA134955499; -.
DR VEuPathDB; HostDB:ENSG00000165819; -.
DR eggNOG; KOG2098; Eukaryota.
DR GeneTree; ENSGT00550000075058; -.
DR HOGENOM; CLU_018702_4_0_1; -.
DR InParanoid; Q86U44; -.
DR OMA; YPDGNSM; -.
DR OrthoDB; 179166at2759; -.
DR PhylomeDB; Q86U44; -.
DR TreeFam; TF323854; -.
DR BRENDA; 2.1.1.348; 2681.
DR PathwayCommons; Q86U44; -.
DR Reactome; R-HSA-72203; Processing of Capped Intron-Containing Pre-mRNA.
DR SignaLink; Q86U44; -.
DR SIGNOR; Q86U44; -.
DR BioGRID-ORCS; 56339; 496 hits in 1175 CRISPR screens.
DR ChiTaRS; METTL3; human.
DR EvolutionaryTrace; Q86U44; -.
DR GeneWiki; METTL3; -.
DR GenomeRNAi; 56339; -.
DR Pharos; Q86U44; Tbio.
DR PRO; PR:Q86U44; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; Q86U44; protein.
DR Bgee; ENSG00000165819; Expressed in right uterine tube and 205 other cell types or tissues.
DR ExpressionAtlas; Q86U44; baseline and differential.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0016604; C:nuclear body; IDA:HPA.
DR GO; GO:0016607; C:nuclear speck; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:1990204; C:oxidoreductase complex; TAS:FlyBase.
DR GO; GO:0036396; C:RNA N6-methyladenosine methyltransferase complex; IDA:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; IDA:UniProtKB.
DR GO; GO:0001734; F:mRNA m(6)A methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB.
DR GO; GO:0008173; F:RNA methyltransferase activity; IDA:UniProtKB.
DR GO; GO:1904047; F:S-adenosyl-L-methionine binding; IDA:UniProtKB.
DR GO; GO:0034644; P:cellular response to UV; IDA:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB.
DR GO; GO:0009048; P:dosage compensation by inactivation of X chromosome; IDA:UniProtKB.
DR GO; GO:0098508; P:endothelial to hematopoietic transition; ISS:UniProtKB.
DR GO; GO:0021861; P:forebrain radial glial cell differentiation; ISS:UniProtKB.
DR GO; GO:0042063; P:gliogenesis; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0061157; P:mRNA destabilization; ISS:UniProtKB.
DR GO; GO:0016556; P:mRNA modification; IDA:UniProt.
DR GO; GO:0006397; P:mRNA processing; IDA:UniProtKB.
DR GO; GO:0000398; P:mRNA splicing, via spliceosome; IMP:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; ISS:UniProtKB.
DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0048477; P:oogenesis; ISS:UniProtKB.
DR GO; GO:1903679; P:positive regulation of cap-independent translational initiation; IMP:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; IMP:UniProtKB.
DR GO; GO:0031053; P:primary miRNA processing; IDA:UniProtKB.
DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB.
DR GO; GO:0051445; P:regulation of meiotic cell cycle; ISS:UniProtKB.
DR GO; GO:0045580; P:regulation of T cell differentiation; ISS:UniProtKB.
DR GO; GO:0001510; P:RNA methylation; IMP:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR GO; GO:0019827; P:stem cell population maintenance; ISS:UniProtKB.
DR Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1.
DR InterPro; IPR025848; MT-A70.
DR InterPro; IPR007757; MT-A70-like.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR PANTHER; PTHR12829; N6-ADENOSINE-METHYLTRANSFERASE; 1.
DR PANTHER; PTHR12829:SF2; N6-ADENOSINE-METHYLTRANSFERASE CATALYTIC SUBUNIT; 1.
DR Pfam; PF05063; MT-A70; 1.
DR SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1.
DR PROSITE; PS51143; MT_A70; 1.
DR PROSITE; PS51563; SAM_MTA70L_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Biological rhythms;
KW Cytoplasm; Differentiation; Direct protein sequencing; DNA damage;
KW Immunity; Innate immunity; Isopeptide bond; Methyltransferase; Nucleus;
KW Oogenesis; Phosphoprotein; Proteomics identification; Reference proteome;
KW RNA-binding; S-adenosyl-L-methionine; Spermatogenesis; Transferase;
KW Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330"
FT CHAIN 2..580
FT /note="N6-adenosine-methyltransferase catalytic subunit"
FT /id="PRO_0000207630"
FT REGION 1..70
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 198..219
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 396..410
FT /note="Gate loop 1"
FT /evidence="ECO:0000303|PubMed:27281194"
FT REGION 450..454
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0007744|PDB:5IL0, ECO:0007744|PDB:5IL1,
FT ECO:0007744|PDB:5IL2"
FT REGION 462..479
FT /note="Interphase loop"
FT /evidence="ECO:0000303|PubMed:27281194"
FT REGION 464..480
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0007744|PDB:5IL0, ECO:0007744|PDB:5IL1,
FT ECO:0007744|PDB:5IL2"
FT REGION 465..478
FT /note="Positively charged region required for RNA-binding"
FT /evidence="ECO:0000269|PubMed:27281194"
FT REGION 507..515
FT /note="Gate loop 2"
FT /evidence="ECO:0000303|PubMed:27281194"
FT MOTIF 210..215
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:29348140"
FT COMPBIAS 13..34
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 43..64
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 377..378
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798,
FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2,
FT ECO:0007744|PDB:5K7U, ECO:0007744|PDB:5K7W,
FT ECO:0007744|PDB:5L6D, ECO:0007744|PDB:5L6E"
FT BINDING 395
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0000269|PubMed:27373337, ECO:0007744|PDB:5IL1,
FT ECO:0007744|PDB:5IL2, ECO:0007744|PDB:5K7U,
FT ECO:0007744|PDB:5K7W"
FT BINDING 513
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0000269|PubMed:27373337, ECO:0007744|PDB:5IL1,
FT ECO:0007744|PDB:5IL2, ECO:0007744|PDB:5K7U,
FT ECO:0007744|PDB:5K7W"
FT BINDING 536..539
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798,
FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2,
FT ECO:0007744|PDB:5K7U, ECO:0007744|PDB:5K7W,
FT ECO:0007744|PDB:5L6D, ECO:0007744|PDB:5L6E"
FT BINDING 549..550
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798,
FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2,
FT ECO:0007744|PDB:5K7U, ECO:0007744|PDB:5K7W,
FT ECO:0007744|PDB:5L6D, ECO:0007744|PDB:5L6E"
FT SITE 438
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2"
FT SITE 441
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2"
FT MOD_RES 2
FT /note="N-acetylserine; alternate"
FT /evidence="ECO:0007744|PubMed:19413330"
FT MOD_RES 2
FT /note="Phosphoserine; alternate"
FT /evidence="ECO:0000269|PubMed:29348140"
FT MOD_RES 43
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29348140,
FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 48
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29348140"
FT MOD_RES 50
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29348140"
FT MOD_RES 219
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29348140,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163"
FT MOD_RES 243
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29348140,
FT ECO:0007744|PubMed:18669648"
FT MOD_RES 348
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:29348140,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 350
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29348140"
FT CROSSLNK 177
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:29506078"
FT CROSSLNK 211
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:29506078"
FT CROSSLNK 212
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:29506078"
FT CROSSLNK 215
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:29506078"
FT VAR_SEQ 1..284
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_007864"
FT VAR_SEQ 486..505
FT /note="GVKGNPQGFNQGLDCDVIVA -> SSSGAQFNRWSTKKNHLISY (in
FT isoform 2)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_007865"
FT VAR_SEQ 506..580
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_007866"
FT VARIANT 406
FT /note="Y -> C (found in patients with large intestine
FT cancer; uncertain significance; does not affect interaction
FT with METTL14; abolished RNA methyltransferase activity in
FT vitro)"
FT /evidence="ECO:0000269|PubMed:27373337"
FT /id="VAR_076859"
FT MUTAGEN 2
FT /note="S->A: Does not affect nuclear localization,
FT interaction with METTL14 or WTAP or catalytic activity;
FT when associated with A-43; A-48 and A-50."
FT /evidence="ECO:0000269|PubMed:29348140"
FT MUTAGEN 43
FT /note="S->A: Does not affect nuclear localization,
FT interaction with METTL14 or WTAP or catalytic activity;
FT when associated with A-2; A-48 and A-50."
FT /evidence="ECO:0000269|PubMed:29348140"
FT MUTAGEN 48
FT /note="S->A: Does not affect nuclear localization,
FT interaction with METTL14 or WTAP or catalytic activity;
FT when associated with A-2; A-43 and A-50."
FT /evidence="ECO:0000269|PubMed:29348140"
FT MUTAGEN 50
FT /note="S->A: Does not affect nuclear localization,
FT interaction with METTL14 or WTAP or catalytic activity;
FT when associated with A-2; A-43 and A-48."
FT /evidence="ECO:0000269|PubMed:29348140"
FT MUTAGEN 177
FT /note="K->R: In 4KR; strongly decreased sumoylation; when
FT associated with 211-R--R-215."
FT /evidence="ECO:0000269|PubMed:29506078"
FT MUTAGEN 211..215
FT /note="KKSRK->GGSGG: Abolishes localization to the
FT nucleus."
FT /evidence="ECO:0000269|PubMed:29348140"
FT MUTAGEN 211..215
FT /note="KKSRK->RRSRR: In 3KR; decreased sumoylation. In 4KR;
FT strongly decreased sumoylation; when associated with R-
FT 177."
FT /evidence="ECO:0000269|PubMed:29506078"
FT MUTAGEN 219
FT /note="S->A: Does not affect nuclear localization,
FT interaction with METTL14 or WTAP or catalytic activity;
FT when associated with A-243 and 348-A--A-350."
FT /evidence="ECO:0000269|PubMed:29348140"
FT MUTAGEN 243
FT /note="S->A: Does not affect nuclear localization,
FT interaction with METTL14 or WTAP or catalytic activity;
FT when associated with A-219 and 348-A--A-350."
FT /evidence="ECO:0000269|PubMed:29348140"
FT MUTAGEN 294
FT /note="C->A: Abolishes methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:27373337"
FT MUTAGEN 326
FT /note="C->A: Abolishes methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:27373337"
FT MUTAGEN 348..350
FT /note="TPS->APA: Does not affect nuclear localization,
FT interaction with METTL14 or WTAP or catalytic activity;
FT when associated with A-219 and A-243."
FT /evidence="ECO:0000269|PubMed:29348140"
FT MUTAGEN 377
FT /note="D->A: Abolishes methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:27281194"
FT MUTAGEN 395..398
FT /note="DPPW->APPA: Loss of function. Abolishes ability to
FT regulate primary miRNA processing. Does not affect ability
FT to promote mRNA translation. Abolishes formation of m6A at
FT DNA damage sites."
FT /evidence="ECO:0000269|PubMed:25799998,
FT ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:27627798,
FT ECO:0000269|PubMed:28297716"
FT MUTAGEN 395
FT /note="D->A: Abolishes methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0000269|PubMed:27373337"
FT MUTAGEN 406
FT /note="Y->A: Strong reduction in methyltransferase
FT activity."
FT /evidence="ECO:0000269|PubMed:27627798"
FT MUTAGEN 462..479
FT /note="QLQRIIRTGRTGHWLNHG->AAAAAA: Impaired RNA-binding and
FT methyltransferase activities."
FT /evidence="ECO:0000269|PubMed:27281194"
FT MUTAGEN 475
FT /note="W->A: Decreased methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:27373337"
FT MUTAGEN 477
FT /note="N->A: Decreased methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:27373337"
FT MUTAGEN 532
FT /note="E->A: Abolishes methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:27281194"
FT MUTAGEN 536
FT /note="R->A: Slight reduction in methyltransferase
FT activity."
FT /evidence="ECO:0000269|PubMed:27281194"
FT MUTAGEN 538
FT /note="H->A: Slight reduction in methyltransferase
FT activity."
FT /evidence="ECO:0000269|PubMed:27281194"
FT MUTAGEN 539
FT /note="N->A: Abolishes methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:27281194"
FT MUTAGEN 549
FT /note="N->A: Slight reduction in methyltransferase
FT activity. Strong reduction in methyltransferase activity;
FT when associated with A-550."
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0000269|PubMed:27627798"
FT MUTAGEN 550
FT /note="Q->A: Slight reduction in methyltransferase
FT activity. Strong reduction in methyltransferase activity;
FT when associated with A-549."
FT /evidence="ECO:0000269|PubMed:27281194,
FT ECO:0000269|PubMed:27627798"
FT CONFLICT 251
FT /note="N -> I (in Ref. 1; AAB71850)"
FT /evidence="ECO:0000305"
FT CONFLICT 263..264
FT /note="KF -> I (in Ref. 1; AAB71850)"
FT /evidence="ECO:0000305"
FT CONFLICT 382
FT /note="D -> V (in Ref. 1; AAB71850)"
FT /evidence="ECO:0000305"
FT CONFLICT 568
FT /note="R -> K (in Ref. 4; AAH52244)"
FT /evidence="ECO:0000305"
FT STRAND 372..376
FT /evidence="ECO:0007829|PDB:5IL2"
FT TURN 378..380
FT /evidence="ECO:0007829|PDB:5IL2"
FT HELIX 383..386
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 390..394
FT /evidence="ECO:0007829|PDB:5IL2"
FT TURN 405..407
FT /evidence="ECO:0007829|PDB:7NID"
FT HELIX 411..416
FT /evidence="ECO:0007829|PDB:5IL2"
FT HELIX 419..422
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 424..432
FT /evidence="ECO:0007829|PDB:5IL2"
FT HELIX 436..446
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 450..460
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 464..466
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 473..477
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 480..489
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 498..506
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 510..512
FT /evidence="ECO:0007829|PDB:5IL2"
FT HELIX 516..524
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 530..534
FT /evidence="ECO:0007829|PDB:5IL2"
FT HELIX 537..539
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 544..548
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 553..555
FT /evidence="ECO:0007829|PDB:5IL2"
FT HELIX 559..568
FT /evidence="ECO:0007829|PDB:5IL2"
FT STRAND 570..572
FT /evidence="ECO:0007829|PDB:7NHG"
SQ SEQUENCE 580 AA; 64474 MW; 63A7F10195A3C6AC CRC64;
MSDTWSSIQA HKKQLDSLRE RLQRRRKQDS GHLDLRNPEA ALSPTFRSDS PVPTAPTSGG
PKPSTASAVP ELATDPELEK KLLHHLSDLA LTLPTDAVSI CLAISTPDAP ATQDGVESLL
QKFAAQELIE VKRGLLQDDA HPTLVTYADH SKLSAMMGAV AEKKGPGEVA GTVTGQKRRA
EQDSTTVAAF ASSLVSGLNS SASEPAKEPA KKSRKHAASD VDLEIESLLN QQSTKEQQSK
KVSQEILELL NTTTAKEQSI VEKFRSRGRA QVQEFCDYGT KEECMKASDA DRPCRKLHFR
RIINKHTDES LGDCSFLNTC FHMDTCKYVH YEIDACMDSE APGSKDHTPS QELALTQSVG
GDSSADRLFP PQWICCDIRY LDVSILGKFA VVMADPPWDI HMELPYGTLT DDEMRRLNIP
VLQDDGFLFL WVTGRAMELG RECLNLWGYE RVDEIIWVKT NQLQRIIRTG RTGHWLNHGK
EHCLVGVKGN PQGFNQGLDC DVIVAEVRST SHKPDEIYGM IERLSPGTRK IELFGRPHNV
QPNWITLGNQ LDGIHLLDPD VVARFKQRYP DGIISKPKNL
//