Q9C0B1 (FTO_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Alpha-ketoglutarate-dependent dioxygenase FTO
EC=1.14.11.-

Alternative name(s):
Fat mass and obesity-associated protein

Gene names

Name:	FTO
Synonyms:	KIAA1752

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	505 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. 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. Ref.6 Ref.9
Cofactor	Binds 1 Fe2+ ion per subunit. Ref.9
Enzyme regulation	Activated by ascorbate. Inhibited by N-oxalylglycine, fumarate and succinate By similarity. Ref.9
Subunit structure	Monomer. May also exist as homodimer By similarity.
Subcellular location	Nucleus By similarity.
Tissue specificity	Ubiquitously expressed, with relatively high expression in adrenal glands and brain; especially in hypothalamus and pituitary. Ref.4 Ref.5
Domain	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. Ref.9
Polymorphism	At least one intronic variation within the gene predisposes to childhood and adult obesity.
Involvement in disease	Growth retardation developmental delay coarse facies early death (GDFD) [MIM:612938]: A severe polymalformation syndrome characterized by postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism. In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate are observed. Early death occurs by the age of 3 years. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10
Sequence similarities	Belongs to the fto family.
Biophysicochemical properties	pH dependence: Optimum pH is 5.5-6. Ref.6
Sequence caution	The sequence BAB21843.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Biological process	DNA damage DNA repair RNA repair
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Obesity
Ligand	Iron Metal-binding
Molecular function	Dioxygenase Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA dealkylation involved in DNA repair Inferred from direct assay Ref.9. Source: UniProtKB RNA repair Inferred from direct assay Ref.6. Source: BHF-UCL adipose tissue development Inferred from electronic annotation. Source: Compara oxidative single-stranded DNA demethylation Inferred from direct assay Ref.9. Source: UniProtKB oxidative single-stranded RNA demethylation Inferred from direct assay Ref.6. Source: BHF-UCL regulation of lipid storage Inferred from electronic annotation. Source: Compara regulation of multicellular organism growth Inferred from electronic annotation. Source: Compara regulation of respiratory system process Inferred from electronic annotation. Source: Compara regulation of white fat cell proliferation Inferred from electronic annotation. Source: Compara temperature homeostasis Inferred from electronic annotation. Source: Compara
Cellular_component	nucleus Inferred from sequence or structural similarity PubMed 17991826. Source: BHF-UCL
Molecular_function	DNA-N1-methyladenine dioxygenase activity Inferred from direct assay Ref.9. Source: UniProtKB ferrous iron binding Inferred from direct assay Ref.9. Source: UniProtKB oxidative DNA demethylase activity Inferred from direct assay Ref.9. Source: UniProtKB oxidative RNA demethylase activity Inferred from direct assay Ref.6. Source: BHF-UCL oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9C0B1-1)

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.

Isoform 2 (identifier: Q9C0B1-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-378: Missing.
     379-413: LRQFWFQGNRYRKCTDWWCQPMAQLEALWKKMEGV → MEWRKVSECNSVEPCREVKKWPYRCIHHGKNFSRM

Note: No experimental confirmation available.

Isoform 3 (identifier: Q9C0B1-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-445: Missing.
     446-455: QNLRREWHAR → MACQGREECW

Note: No experimental confirmation available.

Isoform 4 (identifier: Q9C0B1-4)

The sequence of this isoform differs from the canonical sequence as follows:
     1-399: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 505

505

Alpha-ketoglutarate-dependent dioxygenase FTO

PRO_0000286163

Regions

Region

32 – 327

296

Fe2OG dioxygenase domain

Region

213 – 224

12

Loop L1; predicted to block binding of double-stranded DNA or RNA

Region

231 – 234

4

Substrate binding

Region

316 – 318

3

Alpha-ketoglutarate binding

Sites

Metal binding

231

1

Iron; catalytic

Metal binding

233

1

Iron; catalytic

Metal binding

307

1

Iron; catalytic

Binding site

96

1

Substrate

Binding site

108

1

Substrate

Binding site

205

1

Alpha-ketoglutarate

Binding site

295

1

Alpha-ketoglutarate

Binding site

320

1

Alpha-ketoglutarate

Binding site

322

1

Alpha-ketoglutarate

Amino acid modifications

Modified residue

216

1

N6-acetyllysine Ref.7

Natural variations

Alternative sequence

1 – 445

445

Missing in isoform 3.

VSP_025002

Alternative sequence

1 – 399

399

Missing in isoform 4.

VSP_025003

Alternative sequence

1 – 378

378

Missing in isoform 2.

VSP_025004

Alternative sequence

379 – 413

35

LRQFW…KMEGV → MEWRKVSECNSVEPCREVKK WPYRCIHHGKNFSRM in isoform 2.

VSP_025005

Alternative sequence

446 – 455

10

QNLRREWHAR → MACQGREECW in isoform 3.

VSP_025006

Natural variant

316

1

R → Q in GDFD; has no residual normal activity. Ref.10

VAR_063252

Natural variant

405

1

A → V.
Corresponds to variant rs16952624 [ dbSNP | Ensembl ].

VAR_032078

Experimental info

Mutagenesis

96

1

R → M or W: Almost abolishes enzyme activity. Ref.9

Mutagenesis

108

1

Y → A: Abolishes enzyme activity. Ref.9

Mutagenesis

114

1

F → D: Perturbs interaction between N-terminal and C-terminal domains and strongly reduces enzyme activity. Ref.9

Mutagenesis

234

1

E → P: Abolishes enzyme activity. Ref.9

Mutagenesis

392

1

C → D: Perturbs interaction between N-terminal and C-terminal domains and strongly reduces enzyme activity. Ref.9

Sequence conflict

316

1

R → W in BAB21843. Ref.1

Sequence conflict

316

1

R → W in AAH03583. Ref.3

Sequence conflict

316

1

R → W in AAH30798. Ref.3

Sequence conflict

316

1

R → W in AAI32893. Ref.3

Secondary structure

1

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505

Helix Strand Turn

Details...

Helix

37 – 45

9

Beta strand

49 – 52

4

Helix

54 – 56

3

Helix

59 – 74

16

Helix

85 – 87

3

Beta strand

93 – 101

9

Beta strand

104 – 108

5

Beta strand

111 – 114

4

Helix

131 – 158

28

Helix

190 – 196

7

Beta strand

201 – 207

7

Beta strand

212 – 214

3

Beta strand

219 – 221

3

Beta strand

225 – 231

7

Beta strand

242 – 248

7

Beta strand

269 – 276

8

Beta strand

284 – 289

6

Beta strand

294 – 297

4

Helix

301 – 304

4

Beta strand

305 – 310

6

Beta strand

316 – 322

7

Helix

331 – 341

11

Helix

342 – 344

3

Helix

361 – 377

17

Helix

379 – 384

6

Helix

389 – 391

3

Helix

397 – 421

25

Turn

433 – 438

6

Helix

439 – 456

18

Beta strand

457 – 459

3

Helix

460 – 462

3

Turn

466 – 468

3

Helix

492 – 495

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 29, 2007. Version 3. Checksum: 3498A92C6E6D81B1	FASTA	505	58,282
	10 20 30 40 50 60 MKRTPTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLI LREASSVSEE 70 80 90 100 110 120 LHKEVQEAFL TLHKHGCLFR DLVRIQGKDL LTPVSRILIG NPGCTYKYLN TRLFTVPWPV 130 140 150 160 170 180 KGSNIKHTEA EIAAACETFL KLNDYLQIET IQALEELAAK EKANEDAVPL CMSADFPRVG 190 200 210 220 230 240 MGSSYNGQDE VDIKSRAAYN VTLLNFMDPQ KMPYLKEEPY FGMGKMAVSW HHDENLVDRS 250 260 270 280 290 300 AVAVYSYSCE GPEEESEDDS HLEGRDPDIW HVGFKISWDI ETPGLAIPLH QGDCYFMLDD 310 320 330 340 350 360 LNATHQHCVL AGSQPRFSST HRVAECSTGT LDYILQRCQL ALQNVCDDVD NDDVSLKSFE 370 380 390 400 410 420 PAVLKQGEEI HNEVEFEWLR QFWFQGNRYR KCTDWWCQPM AQLEALWKKM EGVTNAVLHE 430 440 450 460 470 480 VKREGLPVEQ RNEILTAILA SLTARQNLRR EWHARCQSRI ARTLPADQKP ECRPYWEKDD 490 500 ASMPLPFDLT DIVSELRGQL LEAKP
	Isoform 2 [UniParc]. Checksum: 5FA0B71723B0564B	FASTA	127	14,936
	10 20 30 40 50 60 MEWRKVSECN SVEPCREVKK WPYRCIHHGK NFSRMTNAVL HEVKREGLPV EQRNEILTAI 70 80 90 100 110 120 LASLTARQNL RREWHARCQS RIARTLPADQ KPECRPYWEK DDASMPLPFD LTDIVSELRG QLLEAKP
	Isoform 3 [UniParc]. Checksum: 54A786243F09AF34	FASTA	60	6,924
	10 20 30 40 50 60 MACQGREECW CQSRIARTLP ADQKPECRPY WEKDDASMPL PFDLTDIVSE LRGQLLEAKP
	Isoform 4 [UniParc]. Checksum: AFE4D8E4F34B2F74	FASTA	106	12,218
	10 20 30 40 50 60 MAQLEALWKK MEGVTNAVLH EVKREGLPVE QRNEILTAIL ASLTARQNLR REWHARCQSR 70 80 90 100 IARTLPADQK PECRPYWEKD DASMPLPFDL TDIVSELRGQ LLEAKP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro." Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O. DNA Res. 7:347-355(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain.
[2]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Tissue: Brain.
[3]	"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] (ISOFORMS 2; 3 AND 4). Tissue: Cervix, Eye and Lung.
[4]	"Variation in FTO contributes to childhood obesity and severe adult obesity." Dina C., Meyre D., Gallina S., Durand E., Korner A., Jacobson P., Carlsson L.M.S., Kiess W., Vatin V., Lecoeur C., Delplanque J., Vaillant E., Pattou F., Ruiz J., Weill J., Levy-Marchal C., Horber F., Potoczna N. , Hercberg S., Le Stunff C., Bougneres P., Kovacs P., Marre M., Balkau B., Cauchi S., Chevre J.-C., Froguel P. Nat. Genet. 39:724-726(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN PREDISPOSITION OF OBESITY, TISSUE SPECIFICITY.
[5]	"A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity." Frayling T.M., Timpson N.J., Weedon M.N., Zeggini E., Freathy R.M., Lindgren C.M., Perry J.R., Elliott K.S., Lango H., Rayner N.W., Shields B., Harries L.W., Barrett J.C., Ellard S., Groves C.J., Knight B., Patch A.M., Ness A.R. , Ebrahim S., Lawlor D.A., Ring S.M., Ben-Shlomo Y., Jarvelin M.-R., Sovio U., Bennett A.J., Melzer D., Ferrucci L., Loos R.J., Barroso I., Wareham N.J., Karpe F., Owen K.R., Cardon L.R., Walker M., Hitman G.A., Palmer C.N., Doney A.S., Morris A.D., Davey-Smith G., Hattersley A.T., McCarthy M.I. Science 316:889-894(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN PREDISPOSITION OF OBESITY, TISSUE SPECIFICITY.
[6]	"Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO." Jia G., Yang C.G., Yang S., Jian X., Yi C., Zhou Z., He C. FEBS Lett. 582:3313-3319(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES.
[7]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-216, MASS SPECTROMETRY.
[8]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]	"Crystal structure of the FTO protein reveals basis for its substrate specificity." Han Z., Niu T., Chang J., Lei X., Zhao M., Wang Q., Cheng W., Wang J., Feng Y., Chai J. Nature 464:1205-1209(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 32-505 IN COMPLEX WITH IRON IONS; N-OXALYLGLYCINE AND 3-METHYLTHYMIDINE, CATALYTIC ACTIVITY, FUNCTION, COFACTOR, ENZYME REGULATION, MUTAGENESIS OF ARG-96; TYR-108; PHE-114; GLU-234 AND CYS-392, CIRCULAR DICHROISM, DOMAIN.
[10]	"Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations." Boissel S., Reish O., Proulx K., Kawagoe-Takaki H., Sedgwick B., Yeo G.S., Meyre D., Golzio C., Molinari F., Kadhom N., Etchevers H.C., Saudek V., Farooqi I.S., Froguel P., Lindahl T., O'Rahilly S., Munnich A., Colleaux L. Am. J. Hum. Genet. 85:106-111(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GDFD GLN-316, CHARACTERIZATION OF VARIANT GDFD GLN-316.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB051539 mRNA. Translation: BAB21843.1. Different initiation.
AC007347 Genomic DNA. No translation available.
AC007496 Genomic DNA. No translation available.
AC007909 Genomic DNA. No translation available.
BC003583 mRNA. Translation: AAH03583.1.
BC030798 mRNA. Translation: AAH30798.1.
BC132892 mRNA. Translation: AAI32893.1.
BC137091 mRNA. Translation: AAI37092.1.

IPI

IPI00028277.
IPI00845224.
IPI00845477.
IPI00945698.

RefSeq

NP_001073901.1. NM_001080432.2.

UniGene

Hs.528833.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3LFM	X-ray	2.50	A	32-505	[»]

ProteinModelPortal

Q9C0B1.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9C0B1. 2 interactions.

STRING

9606.ENSP00000418823.

PTM databases

PhosphoSite

Q9C0B1.

Polymorphism databases

DMDM

148841515.

Proteomic databases

PaxDb

Q9C0B1.

PRIDE

Q9C0B1.

Protocols and materials databases

DNASU

79068.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000431610; ENSP00000415636; ENSG00000140718.
ENST00000460382; ENSP00000417422; ENSG00000140718.
ENST00000463855; ENSP00000417843; ENSG00000140718.
ENST00000471389; ENSP00000418823; ENSG00000140718.

GeneID

79068.

KEGG

hsa:79068.

UCSC

uc002ehr.3. human.
uc010cbz.3. human.

Organism-specific databases

CTD

79068.

GeneCards

GC16P053737.

H-InvDB

HIX0013037.
HIX0134382.
HIX0204005.

HGNC

HGNC:24678. FTO.

HPA

CAB017123.

MIM

610966. gene.
612938. phenotype.

neXtProt

NX_Q9C0B1.

Orphanet

210144. Lethal polymalformative syndrome, Boissel type.

PharmGKB

PA152208656.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG45792.

HOGENOM

HOG000273870.

HOVERGEN

HBG101847.

InParanoid

Q9C0B1.

OMA

AVYNYSC.

OrthoDB

EOG4SF969.

PhylomeDB

Q9C0B1.

Gene expression databases

ArrayExpress

Q9C0B1.

Bgee

Q9C0B1.

CleanEx

HS_FTO.

Genevestigator

Q9C0B1.

Family and domain databases

InterPro

IPR024366. FTO_C.
IPR024367. FTO_cat_dom.
[Graphical view]

Pfam

PF12934. FTO_CTD. 1 hit.
PF12933. FTO_NTD. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

FTO. human.

GenomeRNAi

79068.

NextBio

67845.

SOURCE

Search...

Entry information

Entry name

FTO_HUMAN

Accession

Primary (citable) accession number: Q9C0B1
Secondary accession number(s): A2RUH1 , B2RNS0, Q0P676, Q7Z785

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 2007
Last sequence update:	May 29, 2007
Last modified:	May 1, 2013
This is version 74 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.