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Protein

Alpha-ketoglutarate-dependent dioxygenase FTO

Gene

Fto

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

Functioni

Dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation. Has highest activity towards single-stranded RNA containing 3-methyluracil, followed by single-stranded DNA containing 3-methylthymine. Has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine. Specifically demethylates N6-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. Requires molecular oxygen, alpha-ketoglutarate and iron. Contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. Contributes to the regulation of body size and body fat accumulation.4 Publications

Catalytic activityi

N6-methyladenosine in mRNA + 2-oxoglutarate + O2 = adenosine in mRNA + formaldehyde + succinate + CO2.By similarity

Cofactori

Fe2+1 PublicationNote: Binds 1 Fe2+ ion per subunit.1 Publication

Enzyme regulationi

Activated by ascorbate. Inhibited by N-oxalylglycine, fumarate and succinate.1 Publication

pH dependencei

Optimum pH is 5.5-6.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei96SubstrateBy similarity1
Binding sitei108SubstrateBy similarity1
Binding sitei202Alpha-ketoglutarateBy similarity1
Metal bindingi228Iron; catalyticBy similarity1
Metal bindingi230Iron; catalyticBy similarity1
Binding sitei292Alpha-ketoglutarateBy similarity1
Metal bindingi304Iron; catalyticBy similarity1
Binding sitei317Alpha-ketoglutarateBy similarity1
Binding sitei319Alpha-ketoglutarateBy similarity1

GO - Molecular functioni

  • DNA-N1-methyladenine dioxygenase activity Source: UniProtKB
  • ferrous iron binding Source: UniProtKB
  • oxidative DNA demethylase activity Source: BHF-UCL
  • oxidative RNA demethylase activity Source: BHF-UCL
  • RNA N6-methyladenosine dioxygenase activity Source: UniProtKB

GO - Biological processi

  • adipose tissue development Source: UniProtKB
  • DNA dealkylation involved in DNA repair Source: BHF-UCL
  • DNA demethylation Source: BHF-UCL
  • oxidative demethylation Source: BHF-UCL
  • oxidative single-stranded DNA demethylation Source: BHF-UCL
  • oxidative single-stranded RNA demethylation Source: BHF-UCL
  • regulation of brown fat cell differentiation Source: MGI
  • regulation of lipid storage Source: UniProtKB
  • regulation of multicellular organism growth Source: UniProtKB
  • regulation of respiratory system process Source: UniProtKB
  • regulation of white fat cell proliferation Source: UniProtKB
  • RNA repair Source: BHF-UCL
  • temperature homeostasis Source: UniProtKB

Keywordsi

Molecular functionDioxygenase, Oxidoreductase
Biological processDNA damage, DNA repair, RNA repair
LigandIron, Metal-binding

Enzyme and pathway databases

ReactomeiR-MMU-73943 Reversal of alkylation damage by DNA dioxygenases

Names & Taxonomyi

Protein namesi
Recommended name:
Alpha-ketoglutarate-dependent dioxygenase FTO (EC:1.14.11.-By similarity)
Alternative name(s):
Fat mass and obesity-associated protein
Protein fatso
Gene namesi
Name:Fto
Synonyms:Kiaa1752
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 8

Organism-specific databases

MGIiMGI:1347093 Fto

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

Nucleus

Pathology & Biotechi

Disruption phenotypei

Elevated perinatal mortality. Mice have normal body weight at birth, but show growth retardation from day 2 onwards, resulting in a weight reduction of 30-40% after 6 weeks, both in males and females. In addition, animals display reduced nose to anus length. Fat mass is reduced by 60% in males and by 23% in females. Lean body mass is reduced by 26% in males and 19% in females. White adipose tissue decreases more and more over time, while brown adipose tissue is not affected. Serum leptin levels are decreased, while serum levels of adiponectin are increased. Mice exhibit significant hyperphagia after correction for body weight. They show increased oxygen consumption, carbon dioxide production and heat generation, indicating increased energy expenditure, in spite of reduced spontaneous locomotor activity. Plasma adrenaline concentrations are significantly increased. Overall glucose metabolism appears normal.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi304H → A: Reduced enzyme activity. 1 Publication1
Mutagenesisi313R → A: Loss of enzyme activity. 1 Publication1
Mutagenesisi367I → A: Reduces enzyme activity by about 60%. 1 Publication1
Mutagenesisi367I → F: Alters protein structure and causes an increase in whole body metabolism, leading to a lean phenotype in adult males, but not in females. 1 Publication1

Keywords - Diseasei

Obesity

Chemistry databases

ChEMBLiCHEMBL3611964

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002861641 – 502Alpha-ketoglutarate-dependent dioxygenase FTOAdd BLAST502

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei213N6-acetyllysineBy similarity1

Keywords - PTMi

Acetylation

Proteomic databases

PaxDbiQ8BGW1
PeptideAtlasiQ8BGW1
PRIDEiQ8BGW1

PTM databases

iPTMnetiQ8BGW1
PhosphoSitePlusiQ8BGW1

Expressioni

Tissue specificityi

Ubiquitous. Detected in brain, brain cortex, hypothalamus, cerebellum, liver, pancreas, heart, kidney, white adipose tissue and skeletal muscle. Most abundant in the brain, particularly in hypothalamic nuclei governing energy balance.2 Publications

Inductioni

Down-regulated in fasting animals.1 Publication

Gene expression databases

BgeeiENSMUSG00000055932
CleanExiMM_FTO
ExpressionAtlasiQ8BGW1 baseline and differential
GenevisibleiQ8BGW1 MM

Interactioni

Subunit structurei

Monomer. May also exist as homodimer.1 Publication

Protein-protein interaction databases

BioGridi204941, 1 interactor
STRINGi10090.ENSMUSP00000068380

Structurei

3D structure databases

ProteinModelPortaliQ8BGW1
SMRiQ8BGW1
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni42 – 324Fe2OG dioxygenase domainBy similarityAdd BLAST283
Regioni210 – 221Loop L1; predicted to block binding of double-stranded DNA or RNABy similarityAdd BLAST12
Regioni228 – 231Substrate bindingBy similarity4
Regioni313 – 315Alpha-ketoglutarate bindingBy similarity3

Domaini

The 3D-structure of the Fe2OG dioxygenase domain is similar to that of the Fe2OG dioxygenase domain found in the bacterial DNA repair dioxygenase alkB and its mammalian orthologs, but sequence similarity is very low. As a consequence, the domain is not detected by protein signature databases (By similarity).By similarity

Sequence similaritiesi

Belongs to the fto family.Curated

Phylogenomic databases

eggNOGiENOG410IJ5C Eukaryota
ENOG4111PKJ LUCA
GeneTreeiENSGT00390000017730
HOVERGENiHBG101847
InParanoidiQ8BGW1
KOiK19469
OMAiPVCIGPD
OrthoDBiEOG091G08LA
PhylomeDBiQ8BGW1
TreeFamiTF333296

Family and domain databases

Gene3Di1.20.58.1470, 1 hit
2.60.120.590, 1 hit
InterProiView protein in InterPro
IPR037151 AlkB-like_sf
IPR032868 FTO
IPR024366 FTO_C
IPR038413 FTO_C_sf
IPR024367 FTO_cat_dom
PANTHERiPTHR31291 PTHR31291, 1 hit
PfamiView protein in Pfam
PF12934 FTO_CTD, 1 hit
PF12933 FTO_NTD, 1 hit
SMARTiView protein in SMART
SM01223 FTO_NTD, 1 hit

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8BGW1-1) [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
MKRVQTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLV
60 70 80 90 100
FREAGSIPEE LHKEVPEAFL TLHKHGCLFR DVVRIQGKDV LTPVSRILIG
110 120 130 140 150
DPGCTYKYLN TRLFTVPWPV KGCTVKYTEA EIAAACQTFL KLNDYLQVET
160 170 180 190 200
IQALEELAVR EKANEDAVPL CMAEFPRAGV GPSCDDEVDL KSRAAYNVTL
210 220 230 240 250
LNFMDPQKMP YLKEEPYFGM GKMAVSWHHD ENLVDRSAVA VYSYSCEGSE
260 270 280 290 300
DESEDESSFE GRDPDTWHVG FKISWDIETP GLTIPLHQGD CYFMLDDLNA
310 320 330 340 350
THQHCVLAGS QPRFSSTHRV AECSTGTLDY ILERCQLALQ NVLNDSDDGD
360 370 380 390 400
VSLKSFDPAV LKQGEEIHNE VEFEWLRQFW FQGNRYKLCT DWWCEPMTHL
410 420 430 440 450
EGLWKKMESM TNAVLREVKR EGLPVEQRSE ILSAILVPLT VRQNLRKEWH
460 470 480 490 500
ARCQSRVVRT LPVQQKPDCR PYWEKDDPSM PLPFDLTDVV SELRGQLLEA

RS
Length:502
Mass (Da):58,007
Last modified:March 1, 2003 - v1
Checksum:i69223B824028D872
GO
Isoform 2 (identifier: Q8BGW1-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     453-502: CQSRVVRTLP...LRGQLLEARS → FVLLRGGVWCPCPSSARPAQRTKVEDILS

Note: No experimental confirmation available.
Show »
Length:481
Mass (Da):55,393
Checksum:iD79A1C3143BEF2D9
GO
Isoform 3 (identifier: Q8BGW1-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     411-413: TNA → VSA
     414-502: Missing.

Note: No experimental confirmation available.
Show »
Length:413
Mass (Da):47,593
Checksum:iA3E62B85C8133963
GO
Isoform 4 (identifier: Q8BGW1-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     296-316: DDLNATHQHCVLAGSQPRFSS → GNVGSLRVGHLWGFEIHFWIL
     317-502: Missing.

Note: No experimental confirmation available.
Show »
Length:316
Mass (Da):36,366
Checksum:iC6C1B6EB7E895140
GO

Sequence cautioni

The sequence BAC98247 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti181G → R in BAC32382 (PubMed:16141072).Curated1
Sequence conflicti384N → S in CAB59324 (PubMed:10501967).Curated1
Sequence conflicti384N → S in BAC98247 (PubMed:14621295).Curated1
Sequence conflicti384N → S in BAC40629 (PubMed:16141072).Curated1
Sequence conflicti384N → S in AAH22222 (PubMed:15489334).Curated1
Sequence conflicti410M → V in BAC98247 (PubMed:14621295).Curated1
Sequence conflicti410M → V in BAC40629 (PubMed:16141072).Curated1
Sequence conflicti410M → V in AAH22222 (PubMed:15489334).Curated1
Sequence conflicti463V → A in BAC40629 (PubMed:16141072).Curated1
Sequence conflicti463V → A in AAH22222 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_025007296 – 316DDLNA…PRFSS → GNVGSLRVGHLWGFEIHFWI L in isoform 4. 1 PublicationAdd BLAST21
Alternative sequenceiVSP_025008317 – 502Missing in isoform 4. 1 PublicationAdd BLAST186
Alternative sequenceiVSP_025009411 – 413TNA → VSA in isoform 3. 1 Publication3
Alternative sequenceiVSP_025010414 – 502Missing in isoform 3. 1 PublicationAdd BLAST89
Alternative sequenceiVSP_025011453 – 502CQSRV…LEARS → FVLLRGGVWCPCPSSARPAQ RTKVEDILS in isoform 2. 1 PublicationAdd BLAST50

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ237917 mRNA Translation: CAB59324.1
AK129437 mRNA Translation: BAC98247.1 Different initiation.
AK036677 mRNA Translation: BAC29533.1
AK040866 mRNA Translation: BAC30724.1
AK045465 mRNA Translation: BAC32382.1
AK049502 mRNA Translation: BAC33780.1
AK088881 mRNA Translation: BAC40629.1
AK161060 mRNA Translation: BAE36177.1
BC022222 mRNA Translation: AAH22222.1
BC057008 mRNA Translation: AAH57008.1
CCDSiCCDS22521.1 [Q8BGW1-1]
RefSeqiNP_036066.2, NM_011936.2 [Q8BGW1-1]
UniGeneiMm.4375

Genome annotation databases

EnsembliENSMUST00000069718; ENSMUSP00000068380; ENSMUSG00000055932 [Q8BGW1-1]
ENSMUST00000125471; ENSMUSP00000147563; ENSMUSG00000055932 [Q8BGW1-4]
ENSMUST00000128081; ENSMUSP00000147548; ENSMUSG00000055932 [Q8BGW1-2]
ENSMUST00000136802; ENSMUSP00000147603; ENSMUSG00000055932 [Q8BGW1-3]
GeneIDi26383
KEGGimmu:26383
UCSCiuc009msq.2 mouse [Q8BGW1-4]
uc009msr.2 mouse [Q8BGW1-3]
uc009mss.2 mouse [Q8BGW1-2]
uc009mst.2 mouse [Q8BGW1-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiFTO_MOUSE
AccessioniPrimary (citable) accession number: Q8BGW1
Secondary accession number(s): Q3TTZ5
, Q6ZPI7, Q8BR68, Q8CB66, Q8R250, Q9QZ13
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 1, 2007
Last sequence update: March 1, 2003
Last modified: March 28, 2018
This is version 113 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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

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