ID FTO_HUMAN Reviewed; 505 AA. AC Q9C0B1; A2RUH1; B2RNS0; Q0P676; Q7Z785; DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot. DT 29-MAY-2007, sequence version 3. DT 25-JAN-2012, entry version 61. DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO; DE EC=1.14.11.-; DE AltName: Full=Fat mass and obesity-associated protein; GN Name=FTO; Synonyms=KIAA1752; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX MEDLINE=21082932; PubMed=11214970; DOI=10.1093/dnares/7.6.347; RA Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XIX. RT The complete sequences of 100 new cDNA clones from brain which code RT for large proteins in vitro."; RL DNA Res. 7:347-355(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC TISSUE=Brain; RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., RA Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 4). RC TISSUE=Cervix, Eye, and Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP INVOLVEMENT IN PREDISPOSITION OF OBESITY, AND TISSUE SPECIFICITY. RX PubMed=17496892; DOI=10.1038/ng2048; RA Dina C., Meyre D., Gallina S., Durand E., Korner A., Jacobson P., RA Carlsson L.M.S., Kiess W., Vatin V., Lecoeur C., Delplanque J., RA Vaillant E., Pattou F., Ruiz J., Weill J., Levy-Marchal C., Horber F., RA Potoczna N., Hercberg S., Le Stunff C., Bougneres P., Kovacs P., RA Marre M., Balkau B., Cauchi S., Chevre J.-C., Froguel P.; RT "Variation in FTO contributes to childhood obesity and severe adult RT obesity."; RL Nat. Genet. 39:724-726(2007). RN [5] RP INVOLVEMENT IN PREDISPOSITION OF OBESITY, AND TISSUE SPECIFICITY. RX PubMed=17434869; DOI=10.1126/science.1141634; RA Frayling T.M., Timpson N.J., Weedon M.N., Zeggini E., Freathy R.M., RA Lindgren C.M., Perry J.R., Elliott K.S., Lango H., Rayner N.W., RA Shields B., Harries L.W., Barrett J.C., Ellard S., Groves C.J., RA Knight B., Patch A.M., Ness A.R., Ebrahim S., Lawlor D.A., Ring S.M., RA Ben-Shlomo Y., Jarvelin M.-R., Sovio U., Bennett A.J., Melzer D., RA Ferrucci L., Loos R.J., Barroso I., Wareham N.J., Karpe F., Owen K.R., RA Cardon L.R., Walker M., Hitman G.A., Palmer C.N., Doney A.S., RA Morris A.D., Davey-Smith G., Hattersley A.T., McCarthy M.I.; RT "A common variant in the FTO gene is associated with body mass index RT and predisposes to childhood and adult obesity."; RL Science 316:889-894(2007). RN [6] RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=18775698; DOI=10.1016/j.febslet.2008.08.019; RA Jia G., Yang C.G., Yang S., Jian X., Yi C., Zhou Z., He C.; RT "Oxidative demethylation of 3-methylthymine and 3-methyluracil in RT single-stranded DNA and RNA by mouse and human FTO."; RL FEBS Lett. 582:3313-3319(2008). RN [7] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-216, AND MASS SPECTROMETRY. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [8] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [9] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 32-505 IN COMPLEX WITH IRON RP IONS; N-OXALYLGLYCINE AND 3-METHYLTHYMIDINE, CATALYTIC ACTIVITY, RP FUNCTION, COFACTOR, ENZYME REGULATION, MUTAGENESIS OF ARG-96; TYR-108; RP PHE-114; GLU-234 AND CYS-392, CIRCULAR DICHROISM, AND DOMAIN. RX PubMed=20376003; DOI=10.1038/nature08921; RA Han Z., Niu T., Chang J., Lei X., Zhao M., Wang Q., Cheng W., Wang J., RA Feng Y., Chai J.; RT "Crystal structure of the FTO protein reveals basis for its substrate RT specificity."; RL Nature 464:1205-1209(2010). RN [10] RP VARIANT GDFD GLN-316, AND CHARACTERIZATION OF VARIANT GDFD GLN-316. RX PubMed=19559399; DOI=10.1016/j.ajhg.2009.06.002; RA Boissel S., Reish O., Proulx K., Kawagoe-Takaki H., Sedgwick B., RA Yeo G.S., Meyre D., Golzio C., Molinari F., Kadhom N., Etchevers H.C., RA Saudek V., Farooqi I.S., Froguel P., Lindahl T., O'Rahilly S., RA Munnich A., Colleaux L.; RT "Loss-of-function mutation in the dioxygenase-encoding FTO gene causes RT severe growth retardation and multiple malformations."; RL Am. J. Hum. Genet. 85:106-111(2009). CC -!- FUNCTION: Dioxygenase that repairs alkylated DNA and RNA by CC oxidative demethylation. Has highest activity towards single- CC stranded RNA containing 3-methyluracil, followed by single- CC stranded DNA containing 3-methylthymine. Has low demethylase CC activity towards single-stranded DNA containing 1-methyladenine or CC 3-methylcytosine. Has no activity towards 1-methylguanine. Has no CC detectable activity towards double-stranded DNA. Requires CC molecular oxygen, alpha-ketoglutarate and iron. Contributes to the CC regulation of the global metabolic rate, energy expenditure and CC energy homeostasis. Contributes to the regulation of body size and CC body fat accumulation. CC -!- COFACTOR: Binds 1 Fe(2+) ion per subunit. CC -!- ENZYME REGULATION: Activated by ascorbate. Inhibited by N- CC oxalylglycine, fumarate and succinate (By similarity). CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC pH dependence: CC Optimum pH is 5.5-6; CC -!- SUBUNIT: Monomer. May also exist as homodimer (By similarity). CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q9C0B1-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9C0B1-2; Sequence=VSP_025004, VSP_025005; CC Note=No experimental confirmation available; CC Name=3; CC IsoId=Q9C0B1-3; Sequence=VSP_025002, VSP_025006; CC Note=No experimental confirmation available; CC Name=4; CC IsoId=Q9C0B1-4; Sequence=VSP_025003; CC Note=No experimental confirmation available; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with relatively high CC expression in adrenal glands and brain; especially in hypothalamus CC and pituitary. CC -!- DOMAIN: The 3D-structure of the Fe2OG dioxygenase domain is CC similar to that of the Fe2OG dioxygenase domain found in the CC bacterial DNA repair dioxygenase alkB and its mammalian orthologs, CC but sequence similarity is very low. As a consequence, the domain CC is not detected by protein signature databases. CC -!- POLYMORPHISM: At least one intronic variation within the gene CC predisposes to childhood and adult obesity. CC -!- DISEASE: Defects in FTO are the cause of growth retardation CC developmental delay coarse facies and early death (GDFD) CC [MIM:612938]. A severe polymalformation syndrome characterized by CC postnatal growth retardation, microcephaly, severe psychomotor CC delay, functional brain deficits and characteristic facial CC dysmorphism. In some patients, structural brain malformations, CC cardiac defects, genital anomalies, and cleft palate are observed. CC Early death occurs by the age of 3 years. CC -!- SIMILARITY: Belongs to the fto family. CC -!- SEQUENCE CAUTION: CC Sequence=BAB21843.1; Type=Erroneous initiation; Note=Translation N-terminally shortened; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- DR EMBL; AB051539; BAB21843.1; ALT_INIT; mRNA. DR EMBL; AC007347; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC007496; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC007909; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC003583; AAH03583.1; -; mRNA. DR EMBL; BC030798; AAH30798.1; -; mRNA. DR EMBL; BC132892; AAI32893.1; -; mRNA. DR EMBL; BC137091; AAI37092.1; -; mRNA. DR IPI; IPI00028277; -. DR IPI; IPI00845224; -. DR IPI; IPI00845477; -. DR IPI; IPI00945698; -. DR RefSeq; NP_001073901.1; NM_001080432.2. DR UniGene; Hs.528833; -. DR PDB; 3LFM; X-ray; 2.50 A; A=32-505. DR PDBsum; 3LFM; -. DR ProteinModelPortal; Q9C0B1; -. DR SMR; Q9C0B1; 30-499. DR IntAct; Q9C0B1; 2. DR STRING; Q9C0B1; -. DR PhosphoSite; Q9C0B1; -. DR DMDM; 148841515; -. DR PRIDE; Q9C0B1; -. DR Ensembl; ENST00000471389; ENSP00000418823; ENSG00000140718. DR GeneID; 79068; -. DR KEGG; hsa:79068; -. DR NMPDR; fig|9606.3.peg.12249; -. DR UCSC; uc002ehr.1; human. DR UCSC; uc010cbz.1; human. DR CTD; 79068; -. DR GeneCards; GC16P053737; -. DR H-InvDB; HIX0013037; -. DR H-InvDB; HIX0030234; -. DR HGNC; HGNC:24678; FTO. DR HPA; CAB017123; -. DR MIM; 610966; gene. DR MIM; 612938; phenotype. DR neXtProt; NX_Q9C0B1; -. DR Orphanet; 210144; Lethal polymalformative syndrome, Boissel type. DR eggNOG; prNOG05326; -. DR GeneTree; ENSGT00390000017730; -. DR HOGENOM; HBG715650; -. DR HOVERGEN; HBG101847; -. DR InParanoid; Q9C0B1; -. DR OMA; HGCLFRD; -. DR OrthoDB; EOG4SF969; -. DR PhylomeDB; Q9C0B1; -. DR NextBio; 67845; -. DR ArrayExpress; Q9C0B1; -. DR Bgee; Q9C0B1; -. DR CleanEx; HS_FTO; -. DR Genevestigator; Q9C0B1; -. DR GO; GO:0005634; C:nucleus; ISS:BHF-UCL. DR GO; GO:0043734; F:DNA-N1-methyladenine dioxygenase activity; IDA:UniProtKB. DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB. DR GO; GO:0035516; F:oxidative DNA demethylase activity; IDA:UniProtKB. DR GO; GO:0035515; F:oxidative RNA demethylase activity; IDA:BHF-UCL. DR GO; GO:0016702; F:oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen; IEA:UniProtKB-KW. DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; IDA:UniProtKB. DR GO; GO:0035552; P:oxidative single-stranded DNA demethylation; IDA:UniProtKB. DR GO; GO:0035553; P:oxidative single-stranded RNA demethylation; IDA:BHF-UCL. DR GO; GO:0042245; P:RNA repair; IDA:BHF-UCL. DR InterPro; IPR024366; FTO_C. DR InterPro; IPR024367; FTO_cat_dom. DR Pfam; PF12934; FTO_CTD; 1. DR Pfam; PF12933; FTO_NTD; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Complete proteome; KW Dioxygenase; Disease mutation; DNA damage; DNA repair; Iron; KW Metal-binding; Nucleus; Obesity; Oxidoreductase; Polymorphism; KW Reference proteome; RNA repair. FT CHAIN 1 505 Alpha-ketoglutarate-dependent dioxygenase FT FTO. FT /FTId=PRO_0000286163. FT REGION 32 327 Fe2OG dioxygenase domain. FT REGION 213 224 Loop L1; predicted to block binding of FT double-stranded DNA or RNA. FT REGION 231 234 Substrate binding. FT REGION 316 318 Alpha-ketoglutarate binding. FT METAL 231 231 Iron; catalytic. FT METAL 233 233 Iron; catalytic. FT METAL 307 307 Iron; catalytic. FT BINDING 96 96 Substrate. FT BINDING 108 108 Substrate. FT BINDING 205 205 Alpha-ketoglutarate. FT BINDING 295 295 Alpha-ketoglutarate. FT BINDING 320 320 Alpha-ketoglutarate. FT BINDING 322 322 Alpha-ketoglutarate. FT MOD_RES 216 216 N6-acetyllysine. FT VAR_SEQ 1 445 Missing (in isoform 3). FT /FTId=VSP_025002. FT VAR_SEQ 1 399 Missing (in isoform 4). FT /FTId=VSP_025003. FT VAR_SEQ 1 378 Missing (in isoform 2). FT /FTId=VSP_025004. FT VAR_SEQ 379 413 LRQFWFQGNRYRKCTDWWCQPMAQLEALWKKMEGV -> ME FT WRKVSECNSVEPCREVKKWPYRCIHHGKNFSRM (in FT isoform 2). FT /FTId=VSP_025005. FT VAR_SEQ 446 455 QNLRREWHAR -> MACQGREECW (in isoform 3). FT /FTId=VSP_025006. FT VARIANT 316 316 R -> Q (in GDFD; has no residual normal FT activity). FT /FTId=VAR_063252. FT VARIANT 405 405 A -> V (in dbSNP:rs16952624). FT /FTId=VAR_032078. FT MUTAGEN 96 96 R->M,W: Almost abolishes enzyme activity. FT MUTAGEN 108 108 Y->A: Abolishes enzyme activity. FT MUTAGEN 114 114 F->D: Perturbs interaction between N- FT terminal and C-terminal domains and FT strongly reduces enzyme activity. FT MUTAGEN 234 234 E->P: Abolishes enzyme activity. FT MUTAGEN 392 392 C->D: Perturbs interaction between N- FT terminal and C-terminal domains and FT strongly reduces enzyme activity. FT CONFLICT 316 316 R -> W (in Ref. 1; BAB21843 and 3; FT AAH03583/AAH30798/AAI32893). FT HELIX 37 45 FT STRAND 49 52 FT HELIX 54 56 FT HELIX 59 74 FT STRAND 93 99 FT STRAND 105 108 FT STRAND 111 114 FT HELIX 131 158 FT HELIX 190 196 FT STRAND 201 207 FT STRAND 212 214 FT STRAND 226 231 FT STRAND 242 248 FT STRAND 269 272 FT STRAND 287 289 FT STRAND 294 297 FT HELIX 301 304 FT STRAND 305 310 FT STRAND 316 322 FT HELIX 331 341 FT HELIX 342 344 FT HELIX 361 365 FT HELIX 369 377 FT HELIX 379 384 FT HELIX 389 391 FT HELIX 397 410 FT HELIX 414 421 FT TURN 433 438 FT HELIX 439 456 FT STRAND 457 459 FT HELIX 460 462 FT TURN 466 468 FT HELIX 492 495 SQ SEQUENCE 505 AA; 58282 MW; 3498A92C6E6D81B1 CRC64; MKRTPTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLI LREASSVSEE LHKEVQEAFL TLHKHGCLFR DLVRIQGKDL LTPVSRILIG NPGCTYKYLN TRLFTVPWPV KGSNIKHTEA EIAAACETFL KLNDYLQIET IQALEELAAK EKANEDAVPL CMSADFPRVG MGSSYNGQDE VDIKSRAAYN VTLLNFMDPQ KMPYLKEEPY FGMGKMAVSW HHDENLVDRS AVAVYSYSCE GPEEESEDDS HLEGRDPDIW HVGFKISWDI ETPGLAIPLH QGDCYFMLDD LNATHQHCVL AGSQPRFSST HRVAECSTGT LDYILQRCQL ALQNVCDDVD NDDVSLKSFE PAVLKQGEEI HNEVEFEWLR QFWFQGNRYR KCTDWWCQPM AQLEALWKKM EGVTNAVLHE VKREGLPVEQ RNEILTAILA SLTARQNLRR EWHARCQSRI ARTLPADQKP ECRPYWEKDD ASMPLPFDLT DIVSELRGQL LEAKP //