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Protein

N6-adenosine-methyltransferase 70 kDa subunit

Gene

METTL3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. 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:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:9409616). 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 (By similarity). 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 (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).By similarity5 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.By similarity

GO - Molecular functioni

  • mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity Source: UniProtKB
  • RNA binding Source: UniProtKB-KW

GO - Biological processi

  • adenosine to inosine editing Source: UniProtKB
  • circadian rhythm Source: UniProtKB
  • gene expression Source: Reactome
  • mRNA destabilization Source: UniProtKB
  • mRNA methylation Source: UniProtKB
  • mRNA processing Source: UniProtKB
  • mRNA splicing, via spliceosome Source: UniProtKB
  • RNA methylation Source: UniProtKB
  • 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_125. Processing of Capped Intron-Containing Pre-mRNA.

Names & Taxonomyi

Protein namesi
Recommended name:
N6-adenosine-methyltransferase 70 kDa subunit (EC:2.1.1.621 Publication)
Short name:
MT-A70
Alternative name(s):
Methyltransferase-like protein 3
Gene namesi
Name:METTL3
Synonyms:MTA70
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:17563. METTL3.

Subcellular locationi

  • Nucleus speckle 1 Publication

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

GO - Cellular componenti

  • MIS complex Source: UniProtKB
  • nuclear speck Source: UniProtKB
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi395 – 3984DPPW → APPA: Loss of function. Abolishes ability to regulate primary miRNA processing. 1 Publication

Organism-specific databases

PharmGKBiPA134955499.

Polymorphism and mutation databases

BioMutaiMETTL3.
DMDMi33301371.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed1 Publication
Chaini2 – 580579N6-adenosine-methyltransferase 70 kDa subunitPRO_0000207630Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserine1 Publication
Modified residuei43 – 431Phosphoserine3 Publications
Modified residuei219 – 2191Phosphoserine1 Publication
Modified residuei243 – 2431Phosphoserine1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiQ86U44.
PaxDbiQ86U44.
PeptideAtlasiQ86U44.
PRIDEiQ86U44.

PTM databases

PhosphoSiteiQ86U44.

Expressioni

Tissue specificityi

Widely expressed at low level. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.1 Publication

Gene expression databases

BgeeiQ86U44.
CleanExiHS_METTL3.
ExpressionAtlasiQ86U44. baseline and differential.
GenevisibleiQ86U44. HS.

Organism-specific databases

HPAiHPA001299.

Interactioni

Subunit structurei

Component of the WMM complex, a N6-methyltransferase complex composed of WTAP, METTL3 and METTL14.2 Publications

Protein-protein interaction databases

BioGridi121139. 4 interactions.
DIPiDIP-60727N.
STRINGi9606.ENSP00000298717.

Structurei

3D structure databases

ProteinModelPortaliQ86U44.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiCOG4725.
GeneTreeiENSGT00550000075058.
HOGENOMiHOG000012669.
HOVERGENiHBG052521.
InParanoidiQ86U44.
KOiK05925.
OMAiHTKLWAM.
OrthoDBiEOG7PZRWV.
PhylomeDBiQ86U44.
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: Q86U44-1) [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
PVPTAPTSGG PKPSTASAVP ELATDPELEK KLLHHLSDLA LTLPTDAVSI
110 120 130 140 150
CLAISTPDAP ATQDGVESLL QKFAAQELIE VKRGLLQDDA HPTLVTYADH
160 170 180 190 200
SKLSAMMGAV AEKKGPGEVA GTVTGQKRRA EQDSTTVAAF ASSLVSGLNS
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 YEIDACMDSE APGSKDHTPS
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):64,474
Last modified:July 25, 2003 - v2
Checksum:i63A7F10195A3C6AC
GO
Isoform 2 (identifier: Q86U44-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-284: Missing.
     486-505: GVKGNPQGFNQGLDCDVIVA → SSSGAQFNRWSTKKNHLISY
     506-580: Missing.

Note: No experimental confirmation available.
Show »
Length:221
Mass (Da):25,479
Checksum:iD95A9087F7B99439
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti251 – 2511N → I in AAB71850 (PubMed:9409616).Curated
Sequence conflicti263 – 2642KF → I in AAB71850 (PubMed:9409616).Curated
Sequence conflicti382 – 3821D → V in AAB71850 (PubMed:9409616).Curated
Sequence conflicti568 – 5681R → K in AAH52244 (PubMed:15489334).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 284284Missing in isoform 2. 1 PublicationVSP_007864Add
BLAST
Alternative sequencei486 – 50520GVKGN…DVIVA → SSSGAQFNRWSTKKNHLISY in isoform 2. 1 PublicationVSP_007865Add
BLAST
Alternative sequencei506 – 58075Missing in isoform 2. 1 PublicationVSP_007866Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF014837 Genomic DNA. Translation: AAB71850.1.
AF283991 Genomic DNA. Translation: AAG13956.1.
AE000658 Genomic DNA. No translation available.
BX247964 mRNA. Translation: CAD62303.1.
BC003031 mRNA. Translation: AAH03031.1.
BC001650 mRNA. Translation: AAH01650.1.
BC052244 mRNA. Translation: AAH52244.1.
CCDSiCCDS32044.1. [Q86U44-1]
RefSeqiNP_062826.2. NM_019852.4. [Q86U44-1]
UniGeneiHs.168799.

Genome annotation databases

EnsembliENST00000298717; ENSP00000298717; ENSG00000165819. [Q86U44-1]
GeneIDi56339.
KEGGihsa:56339.
UCSCiuc001wbb.3. human. [Q86U44-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF014837 Genomic DNA. Translation: AAB71850.1.
AF283991 Genomic DNA. Translation: AAG13956.1.
AE000658 Genomic DNA. No translation available.
BX247964 mRNA. Translation: CAD62303.1.
BC003031 mRNA. Translation: AAH03031.1.
BC001650 mRNA. Translation: AAH01650.1.
BC052244 mRNA. Translation: AAH52244.1.
CCDSiCCDS32044.1. [Q86U44-1]
RefSeqiNP_062826.2. NM_019852.4. [Q86U44-1]
UniGeneiHs.168799.

3D structure databases

ProteinModelPortaliQ86U44.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121139. 4 interactions.
DIPiDIP-60727N.
STRINGi9606.ENSP00000298717.

PTM databases

PhosphoSiteiQ86U44.

Polymorphism and mutation databases

BioMutaiMETTL3.
DMDMi33301371.

Proteomic databases

MaxQBiQ86U44.
PaxDbiQ86U44.
PeptideAtlasiQ86U44.
PRIDEiQ86U44.

Protocols and materials databases

DNASUi56339.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000298717; ENSP00000298717; ENSG00000165819. [Q86U44-1]
GeneIDi56339.
KEGGihsa:56339.
UCSCiuc001wbb.3. human. [Q86U44-1]

Organism-specific databases

CTDi56339.
GeneCardsiGC14M021966.
HGNCiHGNC:17563. METTL3.
HPAiHPA001299.
MIMi612472. gene.
neXtProtiNX_Q86U44.
PharmGKBiPA134955499.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG4725.
GeneTreeiENSGT00550000075058.
HOGENOMiHOG000012669.
HOVERGENiHBG052521.
InParanoidiQ86U44.
KOiK05925.
OMAiHTKLWAM.
OrthoDBiEOG7PZRWV.
PhylomeDBiQ86U44.
TreeFamiTF323854.

Enzyme and pathway databases

ReactomeiREACT_125. Processing of Capped Intron-Containing Pre-mRNA.

Miscellaneous databases

GeneWikiiMETTL3.
GenomeRNAii56339.
NextBioi61981.
PROiQ86U44.
SOURCEiSearch...

Gene expression databases

BgeeiQ86U44.
CleanExiHS_METTL3.
ExpressionAtlasiQ86U44. baseline and differential.
GenevisibleiQ86U44. HS.

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), PROTEIN SEQUENCE OF 48-56; 134-149 AND 509-522, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, CATALYTIC ACTIVITY.
  2. "Full-length cDNA libraries and normalization."
    Li W.B., Gruber C., Jessee J., Polayes D.
    Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
    Tissue: Placenta.
  3. "The DNA sequence and analysis of human chromosome 14."
    Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., Du H.
    , Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., Waterston R., Hood L., Weissenbach J.
    Nature 421:601-607(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  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: Lung and Pancreas.
  5. "A probability-based approach for high-throughput protein phosphorylation analysis and site localization."
    Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.
    Nat. Biotechnol. 24:1285-1292(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  6. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic kidney.
  7. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43; SER-219 AND SER-243, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  8. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
    Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
    Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
  9. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
    Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
    Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Leukemic T-cell.
  10. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
    Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
    Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  11. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  12. Cited for: FUNCTION.
  13. Cited for: IDENTIFICATION IN THE WMM COMPLEX.
  14. Cited for: IDENTIFICATION IN THE WMM COMPLEX.
  15. "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome."
    Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., Ye M., Zou H.
    J. Proteomics 96:253-262(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  16. "N-methyladenosine-dependent regulation of messenger RNA stability."
    Wang X., Lu Z., Gomez A., Hon G.C., Yue Y., Han D., Fu Y., Parisien M., Dai Q., Jia G., Ren B., Pan T., He C.
    Nature 505:117-120(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  17. "N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions."
    Liu N., Dai Q., Zheng G., He C., Parisien M., Pan T.
    Nature 518:560-564(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  18. "N6-methyladenosine marks primary microRNAs for processing."
    Alarcon C.R., Lee H., Goodarzi H., Halberg N., Tavazoie S.F.
    Nature 519:482-485(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF 395-ASP--TRP-398.

Entry informationi

Entry nameiMTA70_HUMAN
AccessioniPrimary (citable) accession number: Q86U44
Secondary accession number(s): O14736, Q86V05, Q9HB32
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 25, 2003
Last sequence update: July 25, 2003
Last modified: June 24, 2015
This is version 108 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. 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.