MET14_MOUSE
ID MET14_MOUSE Reviewed; 456 AA.
AC Q3UIK4; Q6ZPL2; Q80UR9;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 1.
DT 03-AUG-2022, entry version 110.
DE RecName: Full=N6-adenosine-methyltransferase non-catalytic subunit;
DE AltName: Full=Methyltransferase-like protein 14;
GN Name=Mettl14; Synonyms=Kiaa1627;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=14621295; DOI=10.1093/dnares/10.4.167;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: III.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:167-180(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Heart;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=129/Sv; TISSUE=Embryonic stem cell;
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH METTL3.
RX PubMed=24394384; DOI=10.1038/ncb2902;
RA Wang Y., Li Y., Toth J.I., Petroski M.D., Zhang Z., Zhao J.C.;
RT "N-methyladenosine modification destabilizes developmental regulators in
RT embryonic stem cells.";
RL Nat. Cell Biol. 16:191-198(2014).
RN [6]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=28965759; DOI=10.1016/j.cell.2017.09.003;
RA Yoon K.J., Ringeling F.R., Vissers C., Jacob F., Pokrass M.,
RA Jimenez-Cyrus D., Su Y., Kim N.S., Zhu Y., Zheng L., Kim S., Wang X.,
RA Dore L.C., Jin P., Regot S., Zhuang X., Canzar S., He C., Ming G.L.,
RA Song H.;
RT "Temporal control of mammalian cortical neurogenesis by m(6)A
RT methylation.";
RL Cell 0:0-0(2017).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND TISSUE
RP SPECIFICITY.
RX PubMed=28914256; DOI=10.1038/cr.2017.117;
RA Lin Z., Hsu P.J., Xing X., Fang J., Lu Z., Zou Q., Zhang K.J., Zhang X.,
RA Zhou Y., Zhang T., Zhang Y., Song W., Jia G., Yang X., He C., Tong M.H.;
RT "Mettl3-/Mettl14-mediated mRNA N(6)-methyladenosine modulates murine
RT spermatogenesis.";
RL Cell Res. 27:1216-1230(2017).
RN [8]
RP IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=29535189; DOI=10.1101/gad.309146.117;
RA Knuckles P., Lence T., Haussmann I.U., Jacob D., Kreim N., Carl S.H.,
RA Masiello I., Hares T., Villasenor R., Hess D., Andrade-Navarro M.A.,
RA Biggiogera M., Helm M., Soller M., Buehler M., Roignant J.Y.;
RT "Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-
RT binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d.";
RL Genes Dev. 32:415-429(2018).
RN [9]
RP IDENTIFICATION IN THE WMM COMPLEX, AND SUBCELLULAR LOCATION.
RX PubMed=29547716; DOI=10.1016/j.molcel.2018.02.015;
RA Wen J., Lv R., Ma H., Shen H., He C., Wang J., Jiao F., Liu H., Yang P.,
RA Tan L., Lan F., Shi Y.G., He C., Shi Y., Diao J.;
RT "Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell
RT self-renewal.";
RL Mol. Cell 69:1028-1038(2018).
CC -!- FUNCTION: The METTL3-METTL14 heterodimer forms a N6-methyltransferase
CC complex that methylates adenosine residues at the N(6) position of some
CC mRNAs and regulates the circadian clock, differentiation of embryonic
CC stem cells and cortical neurogenesis (PubMed:24394384,
CC PubMed:28965759). In the heterodimer formed with METTL3, METTL14
CC constitutes the RNA-binding scaffold that recognizes the substrate
CC rather than the catalytic core (By similarity). N6-methyladenosine
CC (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some
CC mRNAs, plays a role in mRNA stability and processing (By similarity).
CC M6A acts as a key regulator of mRNA stability by promoting mRNA
CC destabilization and degradation (PubMed:24394384). In embryonic stem
CC cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-
CC promoting transcripts results in transcript destabilization
CC (PubMed:24394384). M6A regulates spermatogonial differentiation and
CC meiosis and is essential for male fertility and spermatogenesis
CC (PubMed:28914256). M6A also regulates cortical neurogenesis: m6A
CC methylation of transcripts related to transcription factors, neural
CC stem cells, the cell cycle and neuronal differentiation during brain
CC development promotes their destabilization and decay, promoting
CC differentiation of radial glial cells (PubMed:28965759).
CC {ECO:0000250|UniProtKB:Q9HCE5, ECO:0000269|PubMed:24394384,
CC ECO:0000269|PubMed:28914256, ECO:0000269|PubMed:28965759}.
CC -!- SUBUNIT: Heterodimer; heterodimerizes with METTL3 to form an
CC antiparallel heterodimer that constitutes an active methyltransferase
CC (By similarity). Component of the WMM complex, a N6-methyltransferase
CC complex composed of a catalytic subcomplex, named MAC, and of an
CC associated subcomplex, named MACOM (PubMed:29535189, PubMed:29547716).
CC The MAC subcomplex is composed of METTL3 and METTL14 (PubMed:29535189,
CC PubMed:29547716). The MACOM subcomplex is composed of WTAP, ZC3H13,
CC CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B)
CC (PubMed:29535189, PubMed:29547716). {ECO:0000250|UniProtKB:Q9HCE5,
CC ECO:0000269|PubMed:29535189, ECO:0000269|PubMed:29547716}.
CC -!- INTERACTION:
CC Q3UIK4; Q8C3P7: Mettl3; NbExp=2; IntAct=EBI-16089028, EBI-8311763;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:24394384,
CC ECO:0000269|PubMed:28914256, ECO:0000269|PubMed:29547716}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q3UIK4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q3UIK4-2; Sequence=VSP_032406;
CC -!- TISSUE SPECIFICITY: Expressed in testis (PubMed:28914256). Highly
CC expressed in radial glial cells during embryonic cortical neurogenesis
CC (PubMed:28965759). {ECO:0000269|PubMed:28914256,
CC ECO:0000269|PubMed:28965759}.
CC -!- DISRUPTION PHENOTYPE: Conditional knockout mice lacking Mettl3 and
CC Mettl14 in germ cells show impaired spermatogenesis, leading to male
CC infertility (PubMed:28914256). Conditional knockout mice lacking
CC Mettl14 in the developing nervous system die by postnatal day 25 due to
CC protracted cell-cycle progression of cortical neural progenitor cells
CC and reduced differentiation of radial glial cells during embryonic
CC cortical neurogenesis (PubMed:28965759). {ECO:0000269|PubMed:28914256,
CC ECO:0000269|PubMed:28965759}.
CC -!- SIMILARITY: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE-
CC ProRule:PRU00489}.
CC -!- CAUTION: The ability of METTL14 to have catalytic activity is unclear
CC and a number of experimental evidence suggests that it has no
CC methyltransferase activity by itself. According to some reports, has
CC some methyltransferase activity in vitro (PubMed:24394384). However,
CC other studies showed that METTL14 constitutes the RNA-binding scaffold
CC that recognizes the substrate rather than the catalytic core. 3D-
CC structure studies showed that METTL14 contains a degenerate active site
CC that is unable to accommodate donor and acceptor substrates.
CC {ECO:0000250|UniProtKB:Q9HCE5, ECO:0000269|PubMed:24394384}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC98219.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AK129409; BAC98219.1; ALT_INIT; mRNA.
DR EMBL; AK146881; BAE27502.1; -; mRNA.
DR EMBL; BC052204; AAH52204.1; -; mRNA.
DR CCDS; CCDS38622.1; -. [Q3UIK4-1]
DR RefSeq; NP_964000.2; NM_201638.2. [Q3UIK4-1]
DR AlphaFoldDB; Q3UIK4; -.
DR SMR; Q3UIK4; -.
DR BioGRID; 229158; 1.
DR ComplexPortal; CPX-1609; WMM N6-adenosine-methyltransferase complex.
DR DIP; DIP-60725N; -.
DR IntAct; Q3UIK4; 2.
DR STRING; 10090.ENSMUSP00000029759; -.
DR iPTMnet; Q3UIK4; -.
DR PhosphoSitePlus; Q3UIK4; -.
DR EPD; Q3UIK4; -.
DR MaxQB; Q3UIK4; -.
DR PaxDb; Q3UIK4; -.
DR PRIDE; Q3UIK4; -.
DR ProteomicsDB; 252537; -. [Q3UIK4-1]
DR ProteomicsDB; 252538; -. [Q3UIK4-2]
DR Antibodypedia; 26610; 135 antibodies from 22 providers.
DR DNASU; 210529; -.
DR Ensembl; ENSMUST00000029759; ENSMUSP00000029759; ENSMUSG00000028114. [Q3UIK4-1]
DR GeneID; 210529; -.
DR KEGG; mmu:210529; -.
DR UCSC; uc008rfi.2; mouse. [Q3UIK4-1]
DR CTD; 57721; -.
DR MGI; MGI:2442926; Mettl14.
DR VEuPathDB; HostDB:ENSMUSG00000028114; -.
DR eggNOG; KOG2097; Eukaryota.
DR GeneTree; ENSGT00550000075003; -.
DR HOGENOM; CLU_046318_1_0_1; -.
DR InParanoid; Q3UIK4; -.
DR OMA; NINKPGH; -.
DR OrthoDB; 788192at2759; -.
DR PhylomeDB; Q3UIK4; -.
DR TreeFam; TF323641; -.
DR BRENDA; 2.1.1.348; 3474.
DR Reactome; R-MMU-72203; Processing of Capped Intron-Containing Pre-mRNA.
DR BioGRID-ORCS; 210529; 28 hits in 71 CRISPR screens.
DR ChiTaRS; Mettl14; mouse.
DR PRO; PR:Q3UIK4; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q3UIK4; protein.
DR Bgee; ENSMUSG00000028114; Expressed in manus and 220 other tissues.
DR ExpressionAtlas; Q3UIK4; baseline and differential.
DR Genevisible; Q3UIK4; MM.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0036396; C:RNA N6-methyladenosine methyltransferase complex; IDA:UniProtKB.
DR GO; GO:0016422; F:mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
DR GO; GO:0021861; P:forebrain radial glial cell differentiation; IMP:UniProtKB.
DR GO; GO:0042063; P:gliogenesis; IMP:UniProtKB.
DR GO; GO:0006402; P:mRNA catabolic process; IMP:UniProtKB.
DR GO; GO:0061157; P:mRNA destabilization; IMP:UniProtKB.
DR GO; GO:0080009; P:mRNA methylation; IDA:UniProtKB.
DR GO; GO:0000398; P:mRNA splicing, via spliceosome; ISS:UniProtKB.
DR GO; GO:1901533; P:negative regulation of hematopoietic progenitor cell differentiation; IMP:ARUK-UCL.
DR GO; GO:0045727; P:positive regulation of translation; ISO:MGI.
DR GO; GO:0001510; P:RNA methylation; IMP:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; IMP:UniProtKB.
DR GO; GO:0019827; P:stem cell population maintenance; IMP:UniProtKB.
DR InterPro; IPR045123; METTL14-like.
DR InterPro; IPR007757; MT-A70-like.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR PANTHER; PTHR13107; PTHR13107; 1.
DR Pfam; PF05063; MT-A70; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51143; MT_A70; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Differentiation; Nucleus; Phosphoprotein;
KW Reference proteome; RNA-binding; Spermatogenesis.
FT CHAIN 1..456
FT /note="N6-adenosine-methyltransferase non-catalytic
FT subunit"
FT /id="PRO_0000325791"
FT REGION 50..75
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 135..136
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT REGION 237..238
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT REGION 245..254
FT /note="Positively charged region required for RNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT REGION 255..258
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT REGION 278..287
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT REGION 297..298
FT /note="Positively charged region required for RNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT REGION 308..312
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT REGION 393..456
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 424..444
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 146
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT SITE 242
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT SITE 245
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT SITE 298
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT SITE 399
FT /note="Interaction with METTL3"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT MOD_RES 399
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9HCE5"
FT VAR_SEQ 286..456
FT /note="EHCLMGIKGTVKRSTDGDFIHANVDIDLIITEEPEIGNIEKPVEIFHIIEHF
FT CLGRRRLHLFGRDSTIRPGWLTVGPTLTNSNYNAETYASYFSAPNSYLTGCTEEIERLR
FT PKSPPPKSKSDRGGGAPRGGGRGGTSAGRGRERNRSNFRGERGGFRGGRGGTHRGGFTP
FT R -> YPHISTGLPPEHSELKVCVLSRQAVLKVIKKLKLAYYHQKIRHQVGDCLLRNVT
FT SEGEPRAQLSS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14621295"
FT /id="VSP_032406"
FT CONFLICT 348
FT /note="G -> E (in Ref. 3; AAH52204)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 456 AA; 52122 MW; C9CB9440B203957F CRC64;
MDSRLQEIRE RQKLRRQLLA QQLGAESADS IGAVLNSKDE QREIAETRET CRASYDTSAP
NSKRKCLDEG ETDEDKVEEY KDELEMQQEE ENLPYEEEIY KDSSTFLKGT QSLNPHNDYC
QHFVDTGHRP QNFIRDVGLA DRFEEYPKLR ELIRLKDELI AKSNTPPMYL QADIEAFDIR
ELTPKFDVIL LEPPLEEYYR ETGITANEKC WTWDDIMKLE IDEIAAPRSF IFLWCGSGEG
LDLGRVCLRK WGYRRCEDIC WIKTNKNNPG KTKTLDPKAV FQRTKEHCLM GIKGTVKRST
DGDFIHANVD IDLIITEEPE IGNIEKPVEI FHIIEHFCLG RRRLHLFGRD STIRPGWLTV
GPTLTNSNYN AETYASYFSA PNSYLTGCTE EIERLRPKSP PPKSKSDRGG GAPRGGGRGG
TSAGRGRERN RSNFRGERGG FRGGRGGTHR GGFTPR
