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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

The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues of some RNAs and regulates the circadian clock, differentiation of embryonic stem cells and primary miRNA processing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:27281194, PubMed:9409616). In the heterodimer formed with METTL14, METTL3 probably constitutes the catalytic core (PubMed:27281194). 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, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, 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). METTL3 also mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998). 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 (PubMed:27117702). Its overexpression in a number of cancer cells suggests that it may participate to cancer cell proliferation by promoting mRNA translation (PubMed:27117702).By similarity9 Publications

Catalytic activityi

S-adenosyl-L-methionine + m7G(5')pppAm = S-adenosyl-L-homocysteine + m7G(5')pppm6Am.2 Publications

Enzyme regulationi

Methyltransferase activity is regulated by miRNAs via a sequence pairing mechanism.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei395 – 3951S-adenosyl-L-methionineCombined sources1 Publication
Binding sitei438 – 4381Interaction with METTL14Combined sources1 Publication
Binding sitei441 – 4411Interaction with METTL14Combined sources1 Publication
Binding sitei513 – 5131S-adenosyl-L-methionineCombined sources1 Publication

GO - Molecular functioni

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

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
  • 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
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

ReactomeiR-HSA-72203. Processing of Capped Intron-Containing Pre-mRNA.

Names & Taxonomyi

Protein namesi
Recommended name:
N6-adenosine-methyltransferase 70 kDa subunit (EC:2.1.1.622 Publications)
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
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:17563. METTL3.

Subcellular locationi

  • Nucleus 2 Publications
  • Nucleus speckle 1 Publication
  • Cytoplasm 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

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi377 – 3771D → A: Abolishes methyltransferase activity. 1 Publication
Mutagenesisi395 – 3984DPPW → APPA: Loss of function. Abolishes ability to regulate primary miRNA processing. Does not affect ability to promote mRNA translation. 2 Publications
Mutagenesisi395 – 3951D → A: Abolishes methyltransferase activity. 1 Publication
Mutagenesisi462 – 47918QLQRI…WLNHG → AAAAAA: Impaired RNA-binding and methyltransferase activities. 1 PublicationAdd
BLAST
Mutagenesisi532 – 5321E → A: Abolishes methyltransferase activity. 1 Publication
Mutagenesisi536 – 5361R → A: Slight reduction in methyltransferase activity. 1 Publication
Mutagenesisi538 – 5381H → A: Slight reduction in methyltransferase activity. 1 Publication
Mutagenesisi539 – 5391N → A: Abolishes methyltransferase activity. 1 Publication
Mutagenesisi549 – 5491N → A: Slight reduction in methyltransferase activity. 1 Publication
Mutagenesisi550 – 5501Q → A: Slight reduction in methyltransferase activity. 1 Publication

Organism-specific databases

PharmGKBiPA134955499.

Polymorphism and mutation databases

BioMutaiMETTL3.
DMDMi33301371.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedCombined sources
Chaini2 – 580579N6-adenosine-methyltransferase 70 kDa subunitPRO_0000207630Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserineCombined sources
Modified residuei43 – 431PhosphoserineCombined sources
Modified residuei219 – 2191PhosphoserineCombined sources
Modified residuei243 – 2431PhosphoserineCombined sources
Modified residuei348 – 3481PhosphothreonineCombined sources

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ86U44.
MaxQBiQ86U44.
PaxDbiQ86U44.
PeptideAtlasiQ86U44.
PRIDEiQ86U44.

PTM databases

iPTMnetiQ86U44.
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

Inductioni

Overexpressed in a number of cancer tissues, such as lung adenocarcinoma and colon adenocarcinoma (PubMed:27117702).1 Publication

Gene expression databases

BgeeiENSG00000165819.
CleanExiHS_METTL3.
ExpressionAtlasiQ86U44. baseline and differential.
GenevisibleiQ86U44. HS.

Organism-specific databases

HPAiHPA001299.

Interactioni

Subunit structurei

Heterodimer; heterodimerizes with METTL14 to form an antiparallel heterodimer that constitutes an active methyltransferase (PubMed:27281194). Component of the WMM complex, a N6-methyltransferase complex composed of WTAP, METTL3 and METTL14 (PubMed:24407421, PubMed:24981863). Interacts with NCBP1/CBP80 (PubMed:27117702). Interacts with EIF4E (PubMed:27117702). Interacts with EIF3B (PubMed:27117702).4 Publications

Protein-protein interaction databases

BioGridi121139. 18 interactions.
DIPiDIP-60727N.
IntActiQ86U44. 10 interactions.
STRINGi9606.ENSP00000298717.

Structurei

Secondary structure

1
580
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi372 – 3765Combined sources
Turni378 – 3803Combined sources
Helixi383 – 3864Combined sources
Beta strandi390 – 3945Combined sources
Helixi411 – 4166Combined sources
Helixi419 – 4224Combined sources
Beta strandi424 – 4329Combined sources
Helixi436 – 44611Combined sources
Beta strandi450 – 46011Combined sources
Beta strandi464 – 4663Combined sources
Beta strandi473 – 4775Combined sources
Beta strandi480 – 48910Combined sources
Beta strandi498 – 5069Combined sources
Beta strandi510 – 5123Combined sources
Helixi516 – 5249Combined sources
Beta strandi530 – 5345Combined sources
Helixi537 – 5393Combined sources
Beta strandi544 – 5485Combined sources
Beta strandi553 – 5553Combined sources
Helixi559 – 56810Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
5IL0X-ray1.88A369-580[»]
5IL1X-ray1.71A369-580[»]
5IL2X-ray1.61A369-580[»]
ProteinModelPortaliQ86U44.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni377 – 3782S-adenosyl-L-methionine bindingCombined sources1 Publication
Regioni396 – 41015Gate loop 11 PublicationAdd
BLAST
Regioni450 – 4545Interaction with METTL14Combined sources1 Publication
Regioni462 – 47918Interphase loop1 PublicationAdd
BLAST
Regioni464 – 48017Interaction with METTL14Combined sources1 PublicationAdd
BLAST
Regioni465 – 47814Positively charged region required for RNA-binding1 PublicationAdd
BLAST
Regioni507 – 5159Gate loop 21 Publication
Regioni536 – 5394S-adenosyl-L-methionine bindingCombined sources1 Publication
Regioni549 – 5502S-adenosyl-L-methionine bindingCombined sources1 Publication

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.1 Publication

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiKOG2098. Eukaryota.
COG4725. LUCA.
GeneTreeiENSGT00550000075058.
HOGENOMiHOG000012669.
HOVERGENiHBG052521.
InParanoidiQ86U44.
KOiK05925.
OMAiHTKLWAM.
OrthoDBiEOG091G07WA.
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.
UCSCiuc001wbc.4. 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

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
5IL0X-ray1.88A369-580[»]
5IL1X-ray1.71A369-580[»]
5IL2X-ray1.61A369-580[»]
ProteinModelPortaliQ86U44.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121139. 18 interactions.
DIPiDIP-60727N.
IntActiQ86U44. 10 interactions.
STRINGi9606.ENSP00000298717.

PTM databases

iPTMnetiQ86U44.
PhosphoSiteiQ86U44.

Polymorphism and mutation databases

BioMutaiMETTL3.
DMDMi33301371.

Proteomic databases

EPDiQ86U44.
MaxQBiQ86U44.
PaxDbiQ86U44.
PeptideAtlasiQ86U44.
PRIDEiQ86U44.

Protocols and materials databases

DNASUi56339.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000298717; ENSP00000298717; ENSG00000165819. [Q86U44-1]
GeneIDi56339.
KEGGihsa:56339.
UCSCiuc001wbc.4. human. [Q86U44-1]

Organism-specific databases

CTDi56339.
GeneCardsiMETTL3.
HGNCiHGNC:17563. METTL3.
HPAiHPA001299.
MIMi612472. gene.
neXtProtiNX_Q86U44.
PharmGKBiPA134955499.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2098. Eukaryota.
COG4725. LUCA.
GeneTreeiENSGT00550000075058.
HOGENOMiHOG000012669.
HOVERGENiHBG052521.
InParanoidiQ86U44.
KOiK05925.
OMAiHTKLWAM.
OrthoDBiEOG091G07WA.
PhylomeDBiQ86U44.
TreeFamiTF323854.

Enzyme and pathway databases

ReactomeiR-HSA-72203. Processing of Capped Intron-Containing Pre-mRNA.

Miscellaneous databases

GeneWikiiMETTL3.
GenomeRNAii56339.
PROiQ86U44.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000165819.
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...

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: September 7, 2016
This is version 119 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

3D-structure, 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

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 one 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.