METL4_HUMAN
ID METL4_HUMAN Reviewed; 472 AA.
AC Q8N3J2; B2RNA1; Q2TAA7; Q9H5U9;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 3.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=N(6)-adenine-specific methyltransferase METTL4 {ECO:0000305};
DE AltName: Full=Methyltransferase-like protein 4 {ECO:0000305};
DE AltName: Full=N(6)-adenine-specific DNA methyltransferase METTL4 {ECO:0000305};
DE EC=2.1.1.72 {ECO:0000305|PubMed:32183942};
DE AltName: Full=snRNA (2'-O-methyladenosine-N(6)-)-methyltransferase METTL4 {ECO:0000305};
DE EC=2.1.1.- {ECO:0000269|PubMed:31913360};
GN Name=METTL4 {ECO:0000303|PubMed:31913360, ECO:0000312|HGNC:HGNC:24726};
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=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D.,
RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J.,
RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L.,
RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A.,
RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C.,
RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS LYS-310 AND LEU-468.
RC TISSUE=Brain, Lung, and Testis;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 137-472, AND VARIANT LEU-468.
RC TISSUE=Lung;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 228-472, AND VARIANT LEU-468.
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF 287-ASP--TRP-290.
RX PubMed=31913360; DOI=10.1038/s41422-019-0270-4;
RA Chen H., Gu L., Orellana E.A., Wang Y., Guo J., Liu Q., Wang L., Shen Z.,
RA Wu H., Gregory R.I., Xing Y., Shi Y.;
RT "METTL4 is an snRNA m6Am methyltransferase that regulates RNA splicing.";
RL Cell Res. 30:544-547(2020).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 287-ASP--TRP-290.
RX PubMed=32183942; DOI=10.1016/j.molcel.2020.02.018;
RA Hao Z., Wu T., Cui X., Zhu P., Tan C., Dou X., Hsu K.W., Lin Y.T.,
RA Peng P.H., Zhang L.S., Gao Y., Hu L., Sun H.L., Zhu A., Liu J., Wu K.J.,
RA He C.;
RT "N6-deoxyadenosine methylation in mammalian mitochondrial DNA.";
RL Mol. Cell 0:0-0(2020).
RN [8]
RP FUNCTION, AND CAUTION.
RX PubMed=32203414; DOI=10.1038/s41589-020-0504-2;
RA Musheev M.U., Baumgaertner A., Krebs L., Niehrs C.;
RT "The origin of genomic N6-methyl-deoxyadenosine in mammalian cells.";
RL Nat. Chem. Biol. 16:630-634(2020).
RN [9]
RP VARIANT PHE-42.
RX PubMed=21248752; DOI=10.1038/nature09639;
RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H.,
RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J.,
RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M.,
RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L.,
RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J.,
RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A.,
RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K.,
RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.;
RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene
RT PBRM1 in renal carcinoma.";
RL Nature 469:539-542(2011).
CC -!- FUNCTION: N(6)-adenine-specific methyltransferase that can methylate
CC both RNAs and DNA (PubMed:31913360, PubMed:32183942). Acts as a N(6)-
CC adenine-specific RNA methyltransferase by catalyzing formation of
CC N6,2'-O-dimethyladenosine (m6A(m)) on internal positions of U2 small
CC nuclear RNA (snRNA): methylates the 6th position of adenine residues
CC with a pre-deposited 2'-O-methylation (PubMed:31913360). Internal
CC m6A(m) methylation of snRNAs regulates RNA splicing (PubMed:31913360).
CC Also able to act as a N(6)-adenine-specific DNA methyltransferase by
CC mediating methylation of DNA on the 6th position of adenine (N(6)-
CC methyladenosine) (PubMed:32183942). The existence of N(6)-
CC methyladenosine (m6A) on DNA is however unclear in mammals, and
CC additional evidences are required to confirm the role of the N(6)-
CC adenine-specific DNA methyltransferase activity of METTL4 in vivo
CC (PubMed:32203414). Acts as a regulator of mitochondrial transcript
CC levels and mitochondrial DNA (mtDNA) copy number by mediating mtDNA
CC N(6)-methylation: m6A on mtDNA reduces transcription by repressing TFAM
CC DNA-binding and bending (PubMed:32183942). N(6)-methyladenosine
CC deposition by METTL4 regulates Polycomb silencing by triggering
CC ubiquitination and degradation of sensor proteins ASXL1 and MPND,
CC leading to inactivation of the PR-DUB complex and subsequent
CC preservation of Polycomb silencing (By similarity).
CC {ECO:0000250|UniProtKB:Q3U034, ECO:0000269|PubMed:31913360,
CC ECO:0000269|PubMed:32183942, ECO:0000269|PubMed:32203414}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 2'-O-methyladenosine in U2 snRNA + S-adenosyl-L-methionine =
CC an N(6)-methyl-2'-O-methyladenosine in U2 snRNA + H(+) + S-adenosyl-
CC L-homocysteine; Xref=Rhea:RHEA:62672, Rhea:RHEA-COMP:16150,
CC Rhea:RHEA-COMP:16151, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:74477, ChEBI:CHEBI:145853;
CC Evidence={ECO:0000269|PubMed:31913360};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62673;
CC Evidence={ECO:0000269|PubMed:31913360};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 2'-deoxyadenosine in DNA + S-adenosyl-L-methionine = an
CC N(6)-methyl-2'-deoxyadenosine in DNA + H(+) + S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:15197, Rhea:RHEA-COMP:12418, Rhea:RHEA-
CC COMP:12419, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:90615, ChEBI:CHEBI:90616; EC=2.1.1.72;
CC Evidence={ECO:0000305|PubMed:32183942};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15198;
CC Evidence={ECO:0000305|PubMed:32183942};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.43 uM for U2 snRNA {ECO:0000269|PubMed:31913360};
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:31913360,
CC ECO:0000269|PubMed:32183942}. Cytoplasm, cytosol
CC {ECO:0000269|PubMed:32183942}. Mitochondrion matrix
CC {ECO:0000269|PubMed:32183942}.
CC -!- SIMILARITY: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE-
CC ProRule:PRU00489}.
CC -!- CAUTION: The existence of N(6)-methyladenosine on DNA is unclear in
CC mammals (PubMed:32203414). According to a report, the majority of N(6)-
CC methyladenosine in DNA originates from RNA catabolism via a nucleotide
CC salvage pathway and is misincorporated by DNA polymerases, arguing
CC against a role as epigenetic DNA mark in mammalian cells
CC (PubMed:32203414). Additional evidences are therefore required to
CC confirm the role of METTL4 as a N(6)-adenine-specific DNA
CC methyltransferase in vivo (PubMed:32203414).
CC {ECO:0000269|PubMed:32203414}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB15520.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AP005136; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471113; EAX01698.1; -; Genomic_DNA.
DR EMBL; BC111020; AAI11021.1; -; mRNA.
DR EMBL; BC136766; AAI36767.1; -; mRNA.
DR EMBL; BC136767; AAI36768.1; -; mRNA.
DR EMBL; AK026670; BAB15520.1; ALT_FRAME; mRNA.
DR EMBL; AL834296; CAD38969.1; -; mRNA.
DR CCDS; CCDS11826.1; -.
DR RefSeq; NP_073751.3; NM_022840.4.
DR AlphaFoldDB; Q8N3J2; -.
DR SMR; Q8N3J2; -.
DR BioGRID; 122334; 24.
DR STRING; 9606.ENSP00000458290; -.
DR iPTMnet; Q8N3J2; -.
DR PhosphoSitePlus; Q8N3J2; -.
DR BioMuta; METTL4; -.
DR DMDM; 269849669; -.
DR MassIVE; Q8N3J2; -.
DR PaxDb; Q8N3J2; -.
DR PeptideAtlas; Q8N3J2; -.
DR PRIDE; Q8N3J2; -.
DR ProteomicsDB; 71807; -.
DR Antibodypedia; 21910; 121 antibodies from 24 providers.
DR DNASU; 64863; -.
DR Ensembl; ENST00000574538.2; ENSP00000458290.1; ENSG00000101574.15.
DR GeneID; 64863; -.
DR KEGG; hsa:64863; -.
DR MANE-Select; ENST00000574538.2; ENSP00000458290.1; NM_022840.5; NP_073751.3.
DR UCSC; uc002klh.5; human.
DR CTD; 64863; -.
DR DisGeNET; 64863; -.
DR GeneCards; METTL4; -.
DR HGNC; HGNC:24726; METTL4.
DR HPA; ENSG00000101574; Low tissue specificity.
DR MIM; 619626; gene.
DR neXtProt; NX_Q8N3J2; -.
DR OpenTargets; ENSG00000101574; -.
DR PharmGKB; PA134916468; -.
DR VEuPathDB; HostDB:ENSG00000101574; -.
DR eggNOG; KOG2356; Eukaryota.
DR GeneTree; ENSGT00390000016237; -.
DR HOGENOM; CLU_027091_1_0_1; -.
DR InParanoid; Q8N3J2; -.
DR OMA; MSVTEQD; -.
DR OrthoDB; 1496188at2759; -.
DR PhylomeDB; Q8N3J2; -.
DR TreeFam; TF314410; -.
DR PathwayCommons; Q8N3J2; -.
DR BioGRID-ORCS; 64863; 10 hits in 1038 CRISPR screens.
DR ChiTaRS; METTL4; human.
DR GenomeRNAi; 64863; -.
DR Pharos; Q8N3J2; Tbio.
DR PRO; PR:Q8N3J2; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; Q8N3J2; protein.
DR Bgee; ENSG00000101574; Expressed in ventricular zone and 143 other tissues.
DR ExpressionAtlas; Q8N3J2; baseline and differential.
DR Genevisible; Q8N3J2; HS.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0008168; F:methyltransferase activity; IBA:GO_Central.
DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR GO; GO:0008173; F:RNA methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0009007; F:site-specific DNA-methyltransferase (adenine-specific) activity; IDA:UniProtKB.
DR GO; GO:0106347; F:U2 snRNA 2'-O-methyladenosine m6 methyltransferase activity; IEA:RHEA.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0032775; P:DNA methylation on adenine; IDA:UniProtKB.
DR GO; GO:1902275; P:regulation of chromatin organization; ISS:UniProtKB.
DR GO; GO:0090296; P:regulation of mitochondrial DNA replication; IMP:UniProtKB.
DR GO; GO:1903108; P:regulation of mitochondrial transcription; IMP:UniProtKB.
DR GO; GO:0043484; P:regulation of RNA splicing; IMP:UniProtKB.
DR GO; GO:0120049; P:snRNA (adenine-N6)-methylation; IDA:UniProtKB.
DR InterPro; IPR002052; DNA_methylase_N6_adenine_CS.
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; PS00092; N6_MTASE; 1.
PE 1: Evidence at protein level;
KW Chromatin regulator; Cytoplasm; Methyltransferase; Mitochondrion; Nucleus;
KW Reference proteome; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..472
FT /note="N(6)-adenine-specific methyltransferase METTL4"
FT /id="PRO_0000251225"
FT VARIANT 42
FT /note="S -> F (found in a renal cell carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:21248752"
FT /id="VAR_064731"
FT VARIANT 163
FT /note="L -> F (in dbSNP:rs12606220)"
FT /id="VAR_027670"
FT VARIANT 230
FT /note="E -> D (in dbSNP:rs34143130)"
FT /id="VAR_056159"
FT VARIANT 310
FT /note="Q -> K (in dbSNP:rs2677879)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_027671"
FT VARIANT 468
FT /note="V -> L (in dbSNP:rs8084295)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17974005"
FT /id="VAR_027672"
FT MUTAGEN 287..290
FT /note="DPPW->APPA: Abolished methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:31913360,
FT ECO:0000269|PubMed:32183942"
FT CONFLICT 153
FT /note="K -> M (in Ref. 4; BAB15520)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 472 AA; 54041 MW; 5A5D77484AF358D7 CRC64;
MSVVHQLSAG WLLDHLSFIN KINYQLHQHH EPCCRKKEFT TSVHFESLQM DSVSSSGVCA
AFIASDSSTK PENDDGGNYE MFTRKFVFRP ELFDVTKPYI TPAVHKECQQ SNEKEDLMNG
VKKEISISII GKKRKRCVVF NQGELDAMEY HTKIRELILD GSLQLIQEGL KSGFLYPLFE
KQDKGSKPIT LPLDACSLSE LCEMAKHLPS LNEMEHQTLQ LVEEDTSVTE QDLFLRVVEN
NSSFTKVITL MGQKYLLPPK SSFLLSDISC MQPLLNYRKT FDVIVIDPPW QNKSVKRSNR
YSYLSPLQIQ QIPIPKLAAP NCLLVTWVTN RQKHLRFIKE ELYPSWSVEV VAEWHWVKIT
NSGEFVFPLD SPHKKPYEGL ILGRVQEKTA LPLRNADVNV LPIPDHKLIV SVPCTLHSHK
PPLAEVLKDY IKPDGEYLEL FARNLQPGWT SWGNEVLKFQ HVDYFIAVES GS
