MET2A_HUMAN
ID MET2A_HUMAN Reviewed; 378 AA.
AC Q96IZ6; A6NNC4; Q9H9G9; Q9NUI8; Q9P0B5;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 5.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=tRNA N(3)-methylcytidine methyltransferase METTL2A {ECO:0000305};
DE EC=2.1.1.- {ECO:0000269|PubMed:34268557, ECO:0000305|PubMed:28655767};
DE AltName: Full=Methyltransferase-like protein 2A {ECO:0000305};
GN Name=METTL2A {ECO:0000303|PubMed:28655767, ECO:0000312|HGNC:HGNC:25755};
GN Synonyms=METTL2; ORFNames=HSPC266;
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3-378 (ISOFORM 1).
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for 300
RT previously undefined genes expressed in CD34+ hematopoietic stem/progenitor
RT cells.";
RL Genome Res. 10:1546-1560(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3-378 (ISOFORM 1).
RC TISSUE=Teratocarcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-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 [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=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 [8]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=28655767; DOI=10.1074/jbc.m117.798298;
RA Xu L., Liu X., Sheng N., Oo K.S., Liang J., Chionh Y.H., Xu J., Ye F.,
RA Gao Y.G., Dedon P.C., Fu X.Y.;
RT "Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and
RT mRNA in mice and humans.";
RL J. Biol. Chem. 292:14695-14703(2017).
RN [9]
RP INTERACTION WITH DALRD3.
RX PubMed=32427860; DOI=10.1038/s41467-020-16321-6;
RA Lentini J.M., Alsaif H.S., Faqeih E., Alkuraya F.S., Fu D.;
RT "DALRD3 encodes a protein mutated in epileptic encephalopathy that targets
RT arginine tRNAs for 3-methylcytosine modification.";
RL Nat. Commun. 11:2510-2510(2020).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=34268557; DOI=10.1093/nar/gkab603;
RA Mao X.L., Li Z.H., Huang M.H., Wang J.T., Zhou J.B., Li Q.R., Xu H.,
RA Wang X.J., Zhou X.L.;
RT "Mutually exclusive substrate selection strategy by human m3C RNA
RT transferases METTL2A and METTL6.";
RL Nucleic Acids Res. 49:8309-8323(2021).
CC -!- FUNCTION: S-adenosyl-L-methionine-dependent methyltransferase that
CC mediates N(3)-methylcytidine modification of residue 32 of the tRNA
CC anticodon loop of tRNA(Thr)(UGU) and tRNA(Arg)(CCU) (PubMed:28655767,
CC PubMed:34268557). N(3)-methylcytidine methylation by METTL2A requires
CC the N6-threonylcarbamoylation of tRNA (t6A37) by the EKC/KEOPS complex
CC as prerequisite (PubMed:34268557). {ECO:0000269|PubMed:28655767,
CC ECO:0000269|PubMed:34268557}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cytidine(32) in tRNA(Thr) + S-adenosyl-L-methionine = H(+) +
CC N(3)-methylcytidine(32) in tRNA(Thr) + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:50960, Rhea:RHEA-COMP:12850, Rhea:RHEA-COMP:12852,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74894, ChEBI:CHEBI:82748;
CC Evidence={ECO:0000269|PubMed:34268557, ECO:0000305|PubMed:28655767};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50961;
CC Evidence={ECO:0000269|PubMed:34268557, ECO:0000305|PubMed:28655767};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cytidine(32) in tRNA(Arg)(CCU) + S-adenosyl-L-methionine =
CC H(+) + N(3)-methylcytidine(32) in tRNA(Arg)(CCU) + S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:60912, Rhea:RHEA-COMP:15710, Rhea:RHEA-
CC COMP:15712, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74894, ChEBI:CHEBI:82748;
CC Evidence={ECO:0000305|PubMed:28655767};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60913;
CC Evidence={ECO:0000305|PubMed:28655767};
CC -!- SUBUNIT: Monomer (PubMed:34268557). Interacts with DALRD3
CC (PubMed:32427860). {ECO:0000269|PubMed:32427860,
CC ECO:0000269|PubMed:34268557}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:34268557}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96IZ6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96IZ6-2; Sequence=VSP_008477;
CC -!- SIMILARITY: Belongs to the methyltransferase superfamily. METL family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB14260.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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; AC008026; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC006985; AAH06985.1; -; mRNA.
DR EMBL; AF161384; AAF28944.1; -; mRNA.
DR EMBL; AK022822; BAB14260.1; ALT_INIT; mRNA.
DR CCDS; CCDS45752.1; -. [Q96IZ6-1]
DR RefSeq; NP_859076.3; NM_181725.3. [Q96IZ6-1]
DR AlphaFoldDB; Q96IZ6; -.
DR SMR; Q96IZ6; -.
DR BioGRID; 130836; 73.
DR IntAct; Q96IZ6; 16.
DR MINT; Q96IZ6; -.
DR STRING; 9606.ENSP00000309610; -.
DR iPTMnet; Q96IZ6; -.
DR PhosphoSitePlus; Q96IZ6; -.
DR BioMuta; METTL2A; -.
DR DMDM; 269849766; -.
DR EPD; Q96IZ6; -.
DR jPOST; Q96IZ6; -.
DR MassIVE; Q96IZ6; -.
DR MaxQB; Q96IZ6; -.
DR PaxDb; Q96IZ6; -.
DR PeptideAtlas; Q96IZ6; -.
DR PRIDE; Q96IZ6; -.
DR ProteomicsDB; 76877; -. [Q96IZ6-1]
DR ProteomicsDB; 76878; -. [Q96IZ6-2]
DR Antibodypedia; 57006; 127 antibodies from 19 providers.
DR DNASU; 339175; -.
DR Ensembl; ENST00000311506.10; ENSP00000309610.6; ENSG00000087995.16. [Q96IZ6-1]
DR GeneID; 339175; -.
DR KEGG; hsa:339175; -.
DR MANE-Select; ENST00000311506.10; ENSP00000309610.6; NM_181725.4; NP_859076.3.
DR UCSC; uc002izv.3; human. [Q96IZ6-1]
DR CTD; 339175; -.
DR GeneCards; METTL2A; -.
DR HGNC; HGNC:25755; METTL2A.
DR HPA; ENSG00000087995; Low tissue specificity.
DR MIM; 618902; gene.
DR neXtProt; NX_Q96IZ6; -.
DR OpenTargets; ENSG00000087995; -.
DR PharmGKB; PA143485532; -.
DR VEuPathDB; HostDB:ENSG00000087995; -.
DR eggNOG; KOG2361; Eukaryota.
DR GeneTree; ENSGT00940000156059; -.
DR HOGENOM; CLU_029724_0_1_1; -.
DR InParanoid; Q96IZ6; -.
DR OMA; PAKWWNL; -.
DR PhylomeDB; Q96IZ6; -.
DR TreeFam; TF323232; -.
DR PathwayCommons; Q96IZ6; -.
DR SignaLink; Q96IZ6; -.
DR BioGRID-ORCS; 339175; 11 hits in 685 CRISPR screens.
DR ChiTaRS; METTL2A; human.
DR GenomeRNAi; 339175; -.
DR Pharos; Q96IZ6; Tdark.
DR PRO; PR:Q96IZ6; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q96IZ6; protein.
DR Bgee; ENSG00000087995; Expressed in colonic epithelium and 105 other tissues.
DR ExpressionAtlas; Q96IZ6; baseline and differential.
DR Genevisible; Q96IZ6; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0052735; F:tRNA (cytosine-3-)-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0030488; P:tRNA methylation; IDA:UniProtKB.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR026113; MeTrfase.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR PANTHER; PTHR22809; PTHR22809; 1.
DR PIRSF; PIRSF037755; Mettl2_prd; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cytoplasm; Methyltransferase;
KW Phosphoprotein; Reference proteome; S-adenosyl-L-methionine; Transferase;
KW tRNA processing.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..378
FT /note="tRNA N(3)-methylcytidine methyltransferase METTL2A"
FT /id="PRO_0000204452"
FT BINDING 78
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 82
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 188
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 213
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 239
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 240
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 260
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6P1Q9"
FT MOD_RES 154
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q6P1Q9"
FT VAR_SEQ 1..136
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_008477"
FT CONFLICT 118
FT /note="E -> K (in Ref. 3; AAF28944)"
FT /evidence="ECO:0000305"
FT CONFLICT 142
FT /note="K -> R (in Ref. 4; BAB14260)"
FT /evidence="ECO:0000305"
FT CONFLICT 155
FT /note="L -> P (in Ref. 2; AAH06985, 3; AAF28944 and 4;
FT BAB14260)"
FT /evidence="ECO:0000305"
FT CONFLICT 262
FT /note="V -> G (in Ref. 3; AAF28944)"
FT /evidence="ECO:0000305"
FT CONFLICT 273
FT /note="K -> R (in Ref. 3; AAF28944)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 378 AA; 43537 MW; 7469B30968C03BAD CRC64;
MAGSYPEGAP AVLADKRQQF GSRFLRDPAR VFHHNAWDNV EWSEEQAAAA ERKVQENSIQ
RVCQEKQVDY EINAHKYWND FYKIHENGFF KDRHWLFTEF PELAPSQNQN HLKDWFLENK
SEVPECRNNE DGPGLIMEEQ HKCSSKSLEH KTQTLPVEEN VTQKISDLEI CADEFPGSSA
TYRILEVGCG VGNTVFPILQ TNNDPGLFVY CCDFSSTAIE LVQTNSEYDP SRCFAFVHDL
CDEEKSYPVP KGSLDIIILI FVLSAIVPDK MQKAINRLSR LLKPGGMMLL RDYGRYDMAQ
LRFKKGQCLS GNFYVRGDGT RVYFFTQEEL DTLFTTAGLE KVQNLVDRRL QVNRGKQLTM
YRVWIQCKYC KPLLSSTS
