ID FTO_MOUSE Reviewed; 502 AA. AC Q8BGW1; Q3TTZ5; Q6ZPI7; Q8BR68; Q8CB66; Q8R250; Q9QZ13; DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 1. DT 19-OCT-2011, entry version 70. DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO; DE EC=1.14.11.-; DE AltName: Full=Fat mass and obesity-associated protein; DE AltName: Full=Protein fatso; GN Name=Fto; Synonyms=Kiaa1752; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi; OC Muroidea; Muridae; Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX MEDLINE=99431665; PubMed=10501967; DOI=10.1007/s003359901144; RA Peters T., Ausmeier K., Ruether U.; RT "Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) RT mouse mutation."; RL Mamm. Genome 10:983-986(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX MEDLINE=22977043; PubMed=14621295; DOI=10.1093/dnares/10.4.167; RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S., RA Saga Y., Nagase T., Ohara O., Koga H.; RT "Prediction of the coding sequences of mouse homologues of KIAA gene: RT III. The complete nucleotide sequences of 500 mouse KIAA-homologous RT cDNAs identified by screening of terminal sequences of cDNA clones RT randomly sampled from size-fractionated libraries."; RL DNA Res. 10:167-180(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 3 AND 4). RC STRAIN=C57BL/6J, and NOD; RC TISSUE=Aorta, Bone, Corpora quadrigemina, Skin, Thymus, and Vein; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., RA Davis M.J., Wilming L.G., Aidinis V., Allen J.E., RA Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., RA Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., RA Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., RA Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., RA di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., RA Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., RA Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., RA Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., RA Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., RA Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., RA Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., RA Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., RA Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., RA Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., RA Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., RA Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., RA Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., RA Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., RA Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., RA Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., RA Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., RA Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., RA Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., RA Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., RA Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., RA Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., RA Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., RA Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., RA Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., RA Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC STRAIN=C57BL/6, and FVB/N; TISSUE=Brain, and Kidney; 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 [5] RP FUNCTION, COFACTOR, ENZYME REGULATION, SUBCELLULAR LOCATION, RP MUTAGENESIS OF HIS-304 AND ARG-313, INDUCTION, AND TISSUE SPECIFICITY. RX PubMed=17991826; DOI=10.1126/science.1151710; RA Gerken T., Girard C.A., Tung Y.C., Webby C.J., Saudek V., RA Hewitson K.S., Yeo G.S., McDonough M.A., Cunliffe S., McNeill L.A., RA Galvanovskis J., Rorsman P., Robins P., Prieur X., Coll A.P., Ma M., RA Jovanovic Z., Farooqi I.S., Sedgwick B., Barroso I., Lindahl T., RA Ponting C.P., Ashcroft F.M., O'Rahilly S., Schofield C.J.; RT "The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent RT nucleic acid demethylase."; RL Science 318:1469-1472(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 DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, FUNCTION, AND TISSUE RP SPECIFICITY. RX PubMed=19234441; DOI=10.1038/nature07848; RA Fischer J., Koch L., Emmerling C., Vierkotten J., Peters T., RA Bruning J.C., Ruther U.; RT "Inactivation of the Fto gene protects from obesity."; RL Nature 458:894-898(2009). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, CIRCULAR DICHROISM, AND RP MUTAGENESIS OF ILE-367. RX PubMed=19680540; DOI=10.1371/journal.pgen.1000599; RA Church C., Lee S., Bagg E.A., McTaggart J.S., Deacon R., Gerken T., RA Lee A., Moir L., Mecinovic J., Quwailid M.M., Schofield C.J., RA Ashcroft F.M., Cox R.D.; RT "A mouse model for the metabolic effects of the human fat mass and RT obesity associated FTO gene."; RL PLoS Genet. 5:E1000599-E1000599(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. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC pH dependence: CC Optimum pH is 5.5-6; CC -!- SUBUNIT: Monomer. May also exist as homodimer. CC -!- SUBCELLULAR LOCATION: Nucleus. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q8BGW1-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8BGW1-2; Sequence=VSP_025011; CC Note=No experimental confirmation available; CC Name=3; CC IsoId=Q8BGW1-3; Sequence=VSP_025009, VSP_025010; CC Note=No experimental confirmation available; CC Name=4; CC IsoId=Q8BGW1-4; Sequence=VSP_025007, VSP_025008; CC Note=No experimental confirmation available; CC -!- TISSUE SPECIFICITY: Ubiquitous. Detected in brain, brain cortex, CC hypothalamus, cerebellum, liver, pancreas, heart, kidney, white CC adipose tissue and skeletal muscle. Most abundant in the brain, CC particularly in hypothalamic nuclei governing energy balance. CC -!- INDUCTION: Down-regulated in fasting animals. 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 (By similarity). CC -!- DISRUPTION PHENOTYPE: Elevated perinatal mortality. Mice have CC normal body weight at birth, but show growth retardation from day CC 2 onwards, resulting in a weight reduction of 30-40% after 6 CC weeks, both in males and females. In addition, animals display CC reduced nose to anus length. Fat mass is reduced by 60% in males CC and by 23% in females. Lean body mass is reduced by 26% in males CC and 19% in females. White adipose tissue decreases more and more CC over time, while brown adipose tissue is not affected. Serum CC leptin levels are decreased, while serum levels of adiponectin are CC increased. Mice exhibit significant hyperphagia after correction CC for body weight. They show increased oxygen consumption, carbon CC dioxide production and heat generation, indicating increased CC energy expenditure, in spite of reduced spontaneous locomotor CC activity. Plasma adrenaline concentrations are significantly CC increased. Overall glucose metabolism appears normal. CC -!- SIMILARITY: Belongs to the fto family. CC -!- SEQUENCE CAUTION: CC Sequence=BAC98247.1; 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; AJ237917; CAB59324.1; -; mRNA. DR EMBL; AK129437; BAC98247.1; ALT_INIT; mRNA. DR EMBL; AK036677; BAC29533.1; -; mRNA. DR EMBL; AK040866; BAC30724.1; -; mRNA. DR EMBL; AK045465; BAC32382.1; -; mRNA. DR EMBL; AK049502; BAC33780.1; -; mRNA. DR EMBL; AK088881; BAC40629.1; -; mRNA. DR EMBL; AK161060; BAE36177.1; -; mRNA. DR EMBL; BC022222; AAH22222.1; -; mRNA. DR EMBL; BC057008; AAH57008.1; -; mRNA. DR IPI; IPI00280462; -. DR IPI; IPI00845534; -. DR IPI; IPI00845571; -. DR IPI; IPI00845590; -. DR RefSeq; NP_036066.2; NM_011936.2. DR UniGene; Mm.4375; -. DR ProteinModelPortal; Q8BGW1; -. DR SMR; Q8BGW1; 30-496. DR STRING; Q8BGW1; -. DR PhosphoSite; Q8BGW1; -. DR PRIDE; Q8BGW1; -. DR Ensembl; ENSMUST00000069718; ENSMUSP00000068380; ENSMUSG00000055932. DR GeneID; 26383; -. DR KEGG; mmu:26383; -. DR UCSC; uc009msq.2; mouse. DR UCSC; uc009msr.2; mouse. DR UCSC; uc009mss.2; mouse. DR UCSC; uc009mst.2; mouse. DR CTD; 79068; -. DR MGI; MGI:1347093; Fto. DR eggNOG; roNOG09408; -. DR GeneTree; ENSGT00390000017730; -. DR HOVERGEN; HBG101847; -. DR InParanoid; Q8BGW1; -. DR OMA; HGCLFRD; -. DR OrthoDB; EOG4SF969; -. DR PhylomeDB; Q8BGW1; -. DR NextBio; 304305; -. DR ArrayExpress; Q8BGW1; -. DR Bgee; Q8BGW1; -. DR CleanEx; MM_FTO; -. DR Genevestigator; Q8BGW1; -. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0043734; F:DNA-N1-methyladenine dioxygenase activity; IDA:UniProtKB. DR GO; GO:0008198; F:ferrous iron binding; ISS:UniProtKB. DR GO; GO:0035516; F:oxidative DNA demethylase activity; IDA:BHF-UCL. 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:0060612; P:adipose tissue development; IMP:UniProtKB. DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; ISS:UniProtKB. DR GO; GO:0035552; P:oxidative single-stranded DNA demethylation; IDA:BHF-UCL. DR GO; GO:0035553; P:oxidative single-stranded RNA demethylation; IDA:BHF-UCL. DR GO; GO:0010883; P:regulation of lipid storage; IMP:UniProtKB. DR GO; GO:0040014; P:regulation of multicellular organism growth; IMP:UniProtKB. DR GO; GO:0044065; P:regulation of respiratory system process; IMP:UniProtKB. DR GO; GO:0070350; P:regulation of white fat cell proliferation; IMP:UniProtKB. DR GO; GO:0042245; P:RNA repair; IDA:BHF-UCL. DR GO; GO:0001659; P:temperature homeostasis; IMP:UniProtKB. 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 Acetylation; Alternative splicing; Complete proteome; Dioxygenase; KW DNA damage; DNA repair; Iron; Metal-binding; Nucleus; Obesity; KW Oxidoreductase; Reference proteome; RNA repair. FT CHAIN 1 502 Alpha-ketoglutarate-dependent dioxygenase FT FTO. FT /FTId=PRO_0000286164. FT REGION 42 324 Fe2OG dioxygenase domain (By similarity). FT REGION 210 221 Loop L1; predicted to block binding of FT double-stranded DNA or RNA (By FT similarity). FT REGION 228 231 Substrate binding (By similarity). FT REGION 313 315 Alpha-ketoglutarate binding (By FT similarity). FT METAL 228 228 Iron; catalytic (By similarity). FT METAL 230 230 Iron; catalytic (By similarity). FT METAL 304 304 Iron; catalytic (By similarity). FT BINDING 96 96 Substrate (By similarity). FT BINDING 108 108 Substrate (By similarity). FT BINDING 202 202 Alpha-ketoglutarate (By similarity). FT BINDING 292 292 Alpha-ketoglutarate (By similarity). FT BINDING 317 317 Alpha-ketoglutarate (By similarity). FT BINDING 319 319 Alpha-ketoglutarate (By similarity). FT MOD_RES 213 213 N6-acetyllysine (By similarity). FT VAR_SEQ 296 316 DDLNATHQHCVLAGSQPRFSS -> GNVGSLRVGHLWGFEI FT HFWIL (in isoform 4). FT /FTId=VSP_025007. FT VAR_SEQ 317 502 Missing (in isoform 4). FT /FTId=VSP_025008. FT VAR_SEQ 411 413 TNA -> VSA (in isoform 3). FT /FTId=VSP_025009. FT VAR_SEQ 414 502 Missing (in isoform 3). FT /FTId=VSP_025010. FT VAR_SEQ 453 502 CQSRVVRTLPVQQKPDCRPYWEKDDPSMPLPFDLTDVVSEL FT RGQLLEARS -> FVLLRGGVWCPCPSSARPAQRTKVEDIL FT S (in isoform 2). FT /FTId=VSP_025011. FT MUTAGEN 304 304 H->A: Reduced enzyme activity. FT MUTAGEN 313 313 R->A: Loss of enzyme activity. FT MUTAGEN 367 367 I->A: Reduces enzyme activity by about FT 60%. FT MUTAGEN 367 367 I->F: Alters protein structure and causes FT an increase in whole body metabolism, FT leading to a lean phenotype in adult FT males, but not in females. FT CONFLICT 181 181 G -> R (in Ref. 3; BAC32382). FT CONFLICT 384 384 N -> S (in Ref. 1; CAB59324, 2; BAC98247, FT 3; BAC40629 and 4; AAH22222). FT CONFLICT 410 410 M -> V (in Ref. 2; BAC98247, 3; BAC40629 FT and 4; AAH22222). FT CONFLICT 463 463 V -> A (in Ref. 3; BAC40629 and 4; FT AAH22222). SQ SEQUENCE 502 AA; 58007 MW; 69223B824028D872 CRC64; MKRVQTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLV FREAGSIPEE LHKEVPEAFL TLHKHGCLFR DVVRIQGKDV LTPVSRILIG DPGCTYKYLN TRLFTVPWPV KGCTVKYTEA EIAAACQTFL KLNDYLQVET IQALEELAVR EKANEDAVPL CMAEFPRAGV GPSCDDEVDL KSRAAYNVTL LNFMDPQKMP YLKEEPYFGM GKMAVSWHHD ENLVDRSAVA VYSYSCEGSE DESEDESSFE GRDPDTWHVG FKISWDIETP GLTIPLHQGD CYFMLDDLNA THQHCVLAGS QPRFSSTHRV AECSTGTLDY ILERCQLALQ NVLNDSDDGD VSLKSFDPAV LKQGEEIHNE VEFEWLRQFW FQGNRYKLCT DWWCEPMTHL EGLWKKMESM TNAVLREVKR EGLPVEQRSE ILSAILVPLT VRQNLRKEWH ARCQSRVVRT LPVQQKPDCR PYWEKDDPSM PLPFDLTDVV SELRGQLLEA RS //