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Protein

N6-adenosine-methyltransferase subunit METTL3

Gene

Mettl3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, editing and mRNA stability (PubMed:25456834, PubMed:24394384, PubMed:25569111). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (PubMed:24209618). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (PubMed:25456834, PubMed:24394384, PubMed:25569111).4 Publications

Catalytic activityi

S-adenosyl-L-methionine + m7G(5')pppAm = S-adenosyl-L-homocysteine + m7G(5')pppm6Am.1 Publication

Enzyme regulationi

Methyltransferase activity is regulated by miRNAs via a sequence pairing mechanism.1 Publication

GO - Molecular functioni

  1. mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity Source: UniProtKB
  2. mRNA (N6-adenosine)-methyltransferase activity Source: MGI
  3. RNA binding Source: UniProtKB-KW

GO - Biological processi

  1. circadian rhythm Source: UniProtKB
  2. mRNA destabilization Source: UniProtKB
  3. mRNA methylation Source: UniProtKB
  4. mRNA modification Source: MGI
  5. mRNA processing Source: UniProtKB
  6. RNA methylation Source: UniProtKB
  7. stem cell maintenance Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Methyltransferase, Transferase

Keywords - Biological processi

Biological rhythms

Keywords - Ligandi

RNA-binding, S-adenosyl-L-methionine

Enzyme and pathway databases

ReactomeiREACT_340895. Processing of Capped Intron-Containing Pre-mRNA.

Names & Taxonomyi

Protein namesi
Recommended name:
N6-adenosine-methyltransferase subunit METTL3 (EC:2.1.1.621 Publication)
Alternative name(s):
Methyltransferase-like protein 3
N6-adenosine-methyltransferase 70 kDa subunit
Short name:
MT-A70
Gene namesi
Name:Mettl3
Synonyms:Mta70
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 14

Organism-specific databases

MGIiMGI:1927165. Mettl3.

Subcellular locationi

  1. Nucleus speckle 2 Publications

  2. Note: Colocalizes with speckles in interphase nuclei. Suggesting that it may be associated with nuclear pre-mRNA splicing components.1 Publication

GO - Cellular componenti

  1. MIS complex Source: UniProtKB
  2. nuclear speck Source: UniProtKB
  3. nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

Embryonic lethality (PubMed:25569111). Blastocysts retain normal morphology and expression of pluripotency markers and yield embryonic stem cells (ESCs) at the expected ratio. However, they fail to adequately terminate their naive state and undergo aberrant and restricted lineage priming at the postimplantation stage, leading to early embryonic lethality (PubMed:25456834, PubMed:25569111). mRNAs show a nearly complete absence of N6-methyladenosine (m6A) methylation (PubMed:25456834, PubMed:25569111). RNAs show defects in splicing and adenosine to inosine editing (PubMed:25569111).2 Publications

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi395 – 3984DPPW → APPA: Loss of activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 580579N6-adenosine-methyltransferase subunit METTL3PRO_0000207631Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserineBy similarity
Modified residuei43 – 431PhosphoserineBy similarity
Modified residuei219 – 2191PhosphoserineBy similarity
Modified residuei243 – 2431PhosphoserineBy similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiQ8C3P7.
PaxDbiQ8C3P7.
PRIDEiQ8C3P7.

PTM databases

PhosphoSiteiQ8C3P7.

Expressioni

Gene expression databases

BgeeiQ8C3P7.
CleanExiMM_METTL3.
ExpressionAtlasiQ8C3P7. baseline and differential.
GenevestigatoriQ8C3P7.

Interactioni

Subunit structurei

Component of the WMM complex, a N6-methyltransferase complex composed of WTAP, METTL3 and METTL14.By similarity

Protein-protein interaction databases

BioGridi207910. 1 interaction.
DIPiDIP-60724N.
IntActiQ8C3P7. 1 interaction.
MINTiMINT-4102524.

Family & Domainsi

Sequence similaritiesi

Belongs to the MT-A70-like family.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG4725.
HOGENOMiHOG000012669.
HOVERGENiHBG052521.
InParanoidiQ8C3P7.
KOiK05925.
OrthoDBiEOG7PZRWV.
PhylomeDBiQ8C3P7.
TreeFamiTF323854.

Family and domain databases

Gene3Di3.40.50.150. 1 hit.
InterProiIPR025848. MT-A70.
IPR007757. MT-A70-like.
IPR029063. SAM-dependent_MTases.
[Graphical view]
PfamiPF05063. MT-A70. 1 hit.
[Graphical view]
SUPFAMiSSF53335. SSF53335. 1 hit.
PROSITEiPS51143. MT_A70. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8C3P7-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSDTWSSIQA HKKQLDSLRE RLQRRRKQDS GHLDLRNPEA ALSPTFRSDS
60 70 80 90 100
PVPTAPTSSG PKPSTTSVAP ELATDPELEK KLLHHLSDLA LTLPTDAVSI
110 120 130 140 150
RLAISTPDAP ATQDGVESLL QKFAAQELIE VKRGLLQDDA HPTLVTYADH
160 170 180 190 200
SKLSAMMGAV ADKKGLGEVA GTIAGQKRRA EQDLTTVTTF ASSLASGLAS
210 220 230 240 250
SASEPAKEPA KKSRKHAASD VDLEIESLLN QQSTKEQQSK KVSQEILELL
260 270 280 290 300
NTTTAKEQSI VEKFRSRGRA QVQEFCDYGT KEECMKASDA DRPCRKLHFR
310 320 330 340 350
RIINKHTDES LGDCSFLNTC FHMDTCKYVH YEIDACVDSE SPGSKEHMPS
360 370 380 390 400
QELALTQSVG GDSSADRLFP PQWICCDIRY LDVSILGKFA VVMADPPWDI
410 420 430 440 450
HMELPYGTLT DDEMRRLNIP VLQDDGFLFL WVTGRAMELG RECLNLWGYE
460 470 480 490 500
RVDEIIWVKT NQLQRIIRTG RTGHWLNHGK EHCLVGVKGN PQGFNQGLDC
510 520 530 540 550
DVIVAEVRST SHKPDEIYGM IERLSPGTRK IELFGRPHNV QPNWITLGNQ
560 570 580
LDGIHLLDPD VVARFKQRYP DGIISKPKNL
Length:580
Mass (Da):64,616
Last modified:July 25, 2003 - v2
Checksum:i0DBDA2392A37A018
GO
Isoform 2 (identifier: Q8C3P7-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     34-106: Missing.
     241-299: Missing.

Note: No experimental confirmation available.

Show »
Length:448
Mass (Da):50,157
Checksum:i95539DAD61854334
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti162 – 1621D → E in AAD33673 (PubMed:11389549).Curated
Sequence conflicti162 – 1621D → E in BAC39385 (PubMed:16141072).Curated
Sequence conflicti471 – 4711R → P in BAB26322 (PubMed:16141072).Curated
Sequence conflicti475 – 4751W → L in BAB26322 (PubMed:16141072).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei34 – 10673Missing in isoform 2. 1 PublicationVSP_007867Add
BLAST
Alternative sequencei241 – 29959Missing in isoform 2. 1 PublicationVSP_007868Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF283992 Genomic DNA. Translation: AAG13957.1.
AF135789 mRNA. Translation: AAD33673.1.
AK009492 mRNA. Translation: BAB26322.1.
AK085189 mRNA. Translation: BAC39385.1.
BC012526 mRNA. Translation: AAH12526.1.
CCDSiCCDS27053.1. [Q8C3P7-1]
RefSeqiNP_062695.2. NM_019721.2.
UniGeneiMm.271759.

Genome annotation databases

GeneIDi56335.
KEGGimmu:56335.
UCSCiuc007tpc.1. mouse. [Q8C3P7-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF283992 Genomic DNA. Translation: AAG13957.1.
AF135789 mRNA. Translation: AAD33673.1.
AK009492 mRNA. Translation: BAB26322.1.
AK085189 mRNA. Translation: BAC39385.1.
BC012526 mRNA. Translation: AAH12526.1.
CCDSiCCDS27053.1. [Q8C3P7-1]
RefSeqiNP_062695.2. NM_019721.2.
UniGeneiMm.271759.

3D structure databases

ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi207910. 1 interaction.
DIPiDIP-60724N.
IntActiQ8C3P7. 1 interaction.
MINTiMINT-4102524.

PTM databases

PhosphoSiteiQ8C3P7.

Proteomic databases

MaxQBiQ8C3P7.
PaxDbiQ8C3P7.
PRIDEiQ8C3P7.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi56335.
KEGGimmu:56335.
UCSCiuc007tpc.1. mouse. [Q8C3P7-1]

Organism-specific databases

CTDi56339.
MGIiMGI:1927165. Mettl3.

Phylogenomic databases

eggNOGiCOG4725.
HOGENOMiHOG000012669.
HOVERGENiHBG052521.
InParanoidiQ8C3P7.
KOiK05925.
OrthoDBiEOG7PZRWV.
PhylomeDBiQ8C3P7.
TreeFamiTF323854.

Enzyme and pathway databases

ReactomeiREACT_340895. Processing of Capped Intron-Containing Pre-mRNA.

Miscellaneous databases

ChiTaRSiMettl3. mouse.
NextBioi312322.
PROiQ8C3P7.
SOURCEiSearch...

Gene expression databases

BgeeiQ8C3P7.
CleanExiMM_METTL3.
ExpressionAtlasiQ8C3P7. baseline and differential.
GenevestigatoriQ8C3P7.

Family and domain databases

Gene3Di3.40.50.150. 1 hit.
InterProiIPR025848. MT-A70.
IPR007757. MT-A70-like.
IPR029063. SAM-dependent_MTases.
[Graphical view]
PfamiPF05063. MT-A70. 1 hit.
[Graphical view]
SUPFAMiSSF53335. SSF53335. 1 hit.
PROSITEiPS51143. MT_A70. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase."
    Bokar J.A., Shambaugh M.E., Polayes D., Matera A.G., Rottman F.M.
    RNA 3:1233-1247(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
    Strain: 129/Sv.
  2. "Expression of genes involved in mammalian meiosis during the transition from egg to embryo."
    Hwang S.-Y., Oh B., Knowles B.B., Solter D., Lee J.-S.
    Mol. Reprod. Dev. 59:144-158(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
    Strain: C57BL/6 X DBA/2.
  3. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Strain: C57BL/6J.
    Tissue: Stomach and Tongue.
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Mammary tumor.
  5. "RNA-methylation-dependent RNA processing controls the speed of the circadian clock."
    Fustin J.M., Doi M., Yamaguchi Y., Hida H., Nishimura S., Yoshida M., Isagawa T., Morioka M.S., Kakeya H., Manabe I., Okamura H.
    Cell 155:793-806(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF 395-ASP--TRP-398.
  6. Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  7. "N-methyladenosine modification destabilizes developmental regulators in embryonic stem cells."
    Wang Y., Li Y., Toth J.I., Petroski M.D., Zhang Z., Zhao J.C.
    Nat. Cell Biol. 16:191-198(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH METTL14.
  8. "m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency."
    Chen T., Hao Y.J., Zhang Y., Li M.M., Wang M., Han W., Wu Y., Lv Y., Hao J., Wang L., Li A., Yang Y., Jin K.X., Zhao X., Li Y., Ping X.L., Lai W.Y., Wu L.G.
    , Jiang G., Wang H.L., Sang L., Wang X.J., Yang Y.G., Zhou Q.
    Cell Stem Cell 0:0-0(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, ENZYME REGULATION.
  9. Cited for: FUNCTION, DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiMTA70_MOUSE
AccessioniPrimary (citable) accession number: Q8C3P7
Secondary accession number(s): Q9CV54, Q9ERS9, Q9WUI4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 25, 2003
Last sequence update: July 25, 2003
Last modified: April 29, 2015
This is version 98 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Caution

While different publications agree on the role of N6-methyladenosine (m6A) on RNA stability and its role in embryonic stem cells (ESCs) pluripotency, the precise function of Mettl3 in ESCs self-renewal is unclear. A first paper reported that Mettl3 promotes self-renewal of ESCs by maintaining the groung state of ESCs (PubMed:24394384). However, opposite conclusions were drawn by publications fromn other groups (PubMed:25456834, PubMed:25569111). The differences may be explained by different experimental conditions (such as cell types or RNAi off-target effects).3 Publications

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.