Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
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

The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N6 position of some RNAs and regulates various processes such as the circadian clock, differentiation of embryonic and haematopoietic stem cells, cortical neurogenesis, response to DNA damage, differentiation of T-cells and primary miRNA processing (PubMed:25456834, PubMed:24394384, PubMed:25569111, PubMed:28809392, PubMed:28792938, PubMed:28869969, PubMed:28965759). In the heterodimer formed with METTL14, METTL3 constitutes the catalytic core (By similarity). N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability, processing, translation efficiency and editing (By similarity). M6A acts as a key regulator of mRNA stability: methylation is completed upon the release of mRNA into the nucleoplasm and promotes mRNA destabilization and degradation (PubMed:28637692). 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). M6A regulates the length of the circadian clock: acts as an 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 regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis (PubMed:28809392, PubMed:28914256). Involved in the response to DNA damage: in response to ultraviolet irradiation, METTL3 rapidly catalyzes the formation of m6A on poly(A) transcripts at DNA damage sites, leading to the recruitment of POLK to DNA damage sites (By similarity). M6A is also required for T-cell homeostasis and differentiation: m6A methylation of transcripts of SOCS family members (SOCS1, SOCS3 and CISH) in naive T-cells promotes mRNA destabilization and degradation, promoting T-cell differentiation (PubMed:28792938). M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells (PubMed:28965759). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (By similarity). METTL3 mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (By similarity). Acts as a positive regulator of mRNA translation independently of the methyltransferase activity: promotes translation by interacting with the translation initiation machinery in the cytoplasm (By similarity).By similarity10 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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei395S-adenosyl-L-methionineBy similarity1
Binding sitei438Interaction with METTL14By similarity1
Binding sitei441Interaction with METTL14By similarity1
Binding sitei513S-adenosyl-L-methionineBy similarity1

GO - Molecular functioni

GO - Biological processi

  • adenosine to inosine editing Source: UniProtKB
  • circadian rhythm Source: UniProtKB
  • mRNA destabilization Source: UniProtKB
  • mRNA methylation Source: UniProtKB
  • mRNA modification Source: MGI
  • mRNA processing Source: UniProtKB
  • mRNA splicing, via spliceosome Source: UniProtKB
  • positive regulation of cap-independent translational initiation Source: UniProtKB
  • primary miRNA methylation Source: UniProtKB
  • primary miRNA processing Source: UniProtKB
  • RNA methylation Source: UniProtKB
  • stem cell population maintenance Source: UniProtKB

Keywordsi

Molecular functionMethyltransferase, RNA-binding, Transferase
Biological processBiological rhythms, Differentiation, DNA damage, Spermatogenesis
LigandS-adenosyl-L-methionine

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:Mettl3Imported
Synonyms:Mta70
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1927165. Mettl3.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, 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). Conditional knockout mice lacking Mettl3 in germ cells show male infertility caused by defects in meiosis at the zygotene stage during spermatogenesis (PubMed:28809392). Conditional knockout mice lacking Mettl3 and Mettl14 in germ cells show impaired spermatogenesis (PubMed:28914256). Conditional knockout mice lacking Mettl3 in T-cells show impaired homeostatic expansion of naive T-cells, T-cells remaining in the naive state for up to 12 weeks, thereby preventing colitis (PubMed:28792938). Naive T-cells show loss of m6A modification leading to increased Socs1, Socs3 and Cish mRNA half-life and protein levels, thereby suppressing the IL-7/STAT5 signaling pathway (PubMed:28792938). Conditional knockout mice lacking Mettl3 in the developing nervous system display protracted cell-cycle progression of cortical neural progenitor cells and reduced differentiation of radial glial cells during embryonic cortical neurogenesis (PubMed:28965759).6 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi395 – 398DPPW → APPA: Loss of activity. 2 Publications4

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00002076312 – 580N6-adenosine-methyltransferase subunit METTL3Add BLAST579

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei43PhosphoserineBy similarity1
Modified residuei219PhosphoserineCombined sources1
Modified residuei243PhosphoserineBy similarity1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ8C3P7.
PaxDbiQ8C3P7.
PeptideAtlasiQ8C3P7.
PRIDEiQ8C3P7.

PTM databases

iPTMnetiQ8C3P7.
PhosphoSitePlusiQ8C3P7.

Expressioni

Tissue specificityi

Present in both germ cells and somatic cells during testis development (at protein level) (PubMed:28809392).2 Publications

Gene expression databases

CleanExiMM_METTL3.

Interactioni

Subunit structurei

Heterodimer; heterodimerizes with METTL14 to form an antiparallel heterodimer that constitutes an active methyltransferase. Component of the WMM complex, a N6-methyltransferase complex composed of WTAP, METTL3 and METTL14. Interacts with NCBP1/CBP80. Interacts with EIF4E. Interacts with EIF3B.By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Mettl14Q3UIK42EBI-8311763,EBI-16089028

GO - Molecular functioni

Protein-protein interaction databases

BioGridi207910. 1 interactor.
DIPiDIP-60724N.
IntActiQ8C3P7. 2 interactors.
MINTiMINT-4102524.
STRINGi10090.ENSMUSP00000022767.

Structurei

3D structure databases

ProteinModelPortaliQ8C3P7.
SMRiQ8C3P7.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni377 – 378S-adenosyl-L-methionine bindingBy similarity2
Regioni396 – 410Gate loop 1By similarityAdd BLAST15
Regioni450 – 454Interaction with METTL14By similarity5
Regioni462 – 479Interphase loopBy similarityAdd BLAST18
Regioni464 – 480Interaction with METTL14By similarityAdd BLAST17
Regioni465 – 478Positively charged region required for RNA-bindingBy similarityAdd BLAST14
Regioni507 – 515Gate loop 2By similarity9
Regioni536 – 539S-adenosyl-L-methionine bindingBy similarity4
Regioni549 – 550S-adenosyl-L-methionine bindingBy similarity2

Domaini

Gate loop 1 and gate loop 2 regions are adjacent to the S-adenosyl-L-homocysteine-binding site and display large conformational changes upon ligand-binding. They may play an important role in adenosine recognition. The interface loop contributes to the heterodimer interaction.By similarity

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiKOG2098. Eukaryota.
COG4725. LUCA.
HOGENOMiHOG000012669.
HOVERGENiHBG052521.
InParanoidiQ8C3P7.
KOiK05925.
PhylomeDBiQ8C3P7.
TreeFamiTF323854.

Family and domain databases

InterProiView protein in InterPro
IPR025848. MT-A70.
IPR007757. MT-A70-like.
IPR029063. SAM-dependent_MTases.
PfamiView protein in Pfam
PF05063. MT-A70. 1 hit.
SUPFAMiSSF53335. SSF53335. 1 hit.
PROSITEiView protein in PROSITE
PS51143. MT_A70. 1 hit.

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)DescriptionActionsGraphical viewLength
Sequence conflicti162D → E in AAD33673 (PubMed:11389549).Curated1
Sequence conflicti162D → E in BAC39385 (PubMed:16141072).Curated1
Sequence conflicti471R → P in BAB26322 (PubMed:16141072).Curated1
Sequence conflicti475W → L in BAB26322 (PubMed:16141072).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_00786734 – 106Missing in isoform 2. 1 PublicationAdd BLAST73
Alternative sequenceiVSP_007868241 – 299Missing in isoform 2. 1 PublicationAdd BLAST59

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

Similar proteinsi

Entry informationi

Entry nameiMTA70_MOUSE
AccessioniPrimary (citable) accession number: Q8C3P7
Secondary accession number(s): Q9CV54, Q9ERS9, Q9WUI4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 25, 2003
Last sequence update: July 25, 2003
Last modified: November 22, 2017
This is version 116 of the entry and version 2 of the sequence. See 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 from 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