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 27-MAR-2024, entry version 142. DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO {ECO:0000305}; DE AltName: Full=Fat mass and obesity-associated protein {ECO:0000303|PubMed:17991826}; DE AltName: Full=Protein fatso {ECO:0000303|PubMed:10501967}; DE AltName: Full=U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO {ECO:0000305}; DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9C0B1}; DE AltName: Full=U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO {ECO:0000305}; DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9C0B1}; DE AltName: Full=mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO {ECO:0000305}; DE Short=m6A(m)-demethylase FTO {ECO:0000305}; DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9C0B1}; DE AltName: Full=mRNA N(6)-methyladenosine demethylase FTO {ECO:0000305}; DE EC=1.14.11.53 {ECO:0000305|PubMed:23817550}; DE AltName: Full=tRNA N1-methyl adenine demethylase FTO {ECO:0000305}; DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9C0B1}; GN Name=Fto {ECO:0000303|PubMed:10501967, ECO:0000312|MGI:MGI:1347093}; GN Synonyms=Kiaa1752 {ECO:0000303|PubMed:14621295}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX 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) mouse RT mutation."; RL Mamm. Genome 10:983-986(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX 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: III. RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs RT identified by screening of terminal sequences of cDNA clones randomly RT 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., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., 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., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., 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/6J, 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION, COFACTOR, ACTIVITY REGULATION, SUBCELLULAR LOCATION, MUTAGENESIS RP 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., Hewitson K.S., RA Yeo G.S., McDonough M.A., Cunliffe S., McNeill L.A., Galvanovskis J., RA Rorsman P., Robins P., Prieur X., Coll A.P., Ma M., Jovanovic Z., RA Farooqi I.S., Sedgwick B., Barroso I., Lindahl T., Ponting C.P., RA Ashcroft F.M., O'Rahilly S., Schofield C.J.; RT "The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic RT 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 single- RT 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., Bruning J.C., RA 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., Lee A., RA Moir L., Mecinovic J., Quwailid M.M., Schofield C.J., Ashcroft F.M., RA Cox R.D.; RT "A mouse model for the metabolic effects of the human fat mass and obesity RT associated FTO gene."; RL PLoS Genet. 5:E1000599-E1000599(2009). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Lung, Spleen, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [10] RP FUNCTION. RX PubMed=21076408; DOI=10.1038/ng.713; RA Church C., Moir L., McMurray F., Girard C., Banks G.T., Teboul L., RA Wells S., Bruening J.C., Nolan P.M., Ashcroft F.M., Cox R.D.; RT "Overexpression of Fto leads to increased food intake and results in RT obesity."; RL Nat. Genet. 42:1086-1092(2010). RN [11] RP CAUTION. RX PubMed=24807221; DOI=10.1016/j.cmet.2014.04.009; RA Stratigopoulos G., Martin Carli J.F., O'Day D.R., Wang L., Leduc C.A., RA Lanzano P., Chung W.K., Rosenbaum M., Egli D., Doherty D.A., Leibel R.L.; RT "Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes RT increased adiposity in mice."; RL Cell Metab. 19:767-779(2014). RN [12] RP CAUTION. RX PubMed=24646999; DOI=10.1038/nature13138; RA Smemo S., Tena J.J., Kim K.H., Gamazon E.R., Sakabe N.J., Gomez-Marin C., RA Aneas I., Credidio F.L., Sobreira D.R., Wasserman N.F., Lee J.H., RA Puviindran V., Tam D., Shen M., Son J.E., Vakili N.A., Sung H.K., RA Naranjo S., Acemel R.D., Manzanares M., Nagy A., Cox N.J., Hui C.C., RA Gomez-Skarmeta J.L., Nobrega M.A.; RT "Obesity-associated variants within FTO form long-range functional RT connections with IRX3."; RL Nature 507:371-375(2014). RN [13] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=23817550; DOI=10.1038/nn.3449; RA Hess M.E., Hess S., Meyer K.D., Verhagen L.A., Koch L., Broenneke H.S., RA Dietrich M.O., Jordan S.D., Saletore Y., Elemento O., Belgardt B.F., RA Franz T., Horvath T.L., Ruether U., Jaffrey S.R., Kloppenburg P., RA Bruening J.C.; RT "The fat mass and obesity associated gene (Fto) regulates activity of the RT dopaminergic midbrain circuitry."; RL Nat. Neurosci. 16:1042-1048(2013). RN [14] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=23300482; DOI=10.1371/journal.pgen.1003166; RA McMurray F., Church C.D., Larder R., Nicholson G., Wells S., Teboul L., RA Tung Y.C., Rimmington D., Bosch F., Jimenez V., Yeo G.S., O'Rahilly S., RA Ashcroft F.M., Coll A.P., Cox R.D.; RT "Adult onset global loss of the fto gene alters body composition and RT metabolism in the mouse."; RL PLoS Genet. 9:E1003166-E1003166(2013). RN [15] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=28002401; DOI=10.1038/nature21022; RA Mauer J., Luo X., Blanjoie A., Jiao X., Grozhik A.V., Patil D.P., RA Linder B., Pickering B.F., Vasseur J.J., Chen Q., Gross S.S., Elemento O., RA Debart F., Kiledjian M., Jaffrey S.R.; RT "Reversible methylation of m6Am in the 5' cap controls mRNA stability."; RL Nature 541:371-375(2017). CC -!- FUNCTION: RNA demethylase that mediates oxidative demethylation of CC different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a CC regulator of fat mass, adipogenesis and energy homeostasis CC (PubMed:17991826, PubMed:18775698, PubMed:28002401). Specifically CC demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent CC internal modification of messenger RNA (mRNA) in higher eukaryotes CC (PubMed:28002401). M6A demethylation by FTO affects mRNA expression and CC stability (By similarity). Also able to demethylate m6A in U6 small CC nuclear RNA (snRNA) (By similarity). Mediates demethylation of N(6),2'- CC O-dimethyladenosine cap (m6A(m)), by demethylating the N(6)- CC methyladenosine at the second transcribed position of mRNAs and U6 CC snRNA (PubMed:28002401). Demethylation of m6A(m) in the 5'-cap by FTO CC affects mRNA stability by promoting susceptibility to decapping (By CC similarity). Also acts as a tRNA demethylase by removing N(1)- CC methyladenine from various tRNAs (By similarity). Has no activity CC towards 1-methylguanine (By similarity). Has no detectable activity CC towards double-stranded DNA (By similarity). Also able to repair CC alkylated DNA and RNA by oxidative demethylation: demethylates single- CC stranded RNA containing 3-methyluracil, single-stranded DNA containing CC 3-methylthymine and has low demethylase activity towards single- CC stranded DNA containing 1-methyladenine or 3-methylcytosine CC (PubMed:17991826, PubMed:18775698). Ability to repair alkylated DNA and CC RNA is however unsure in vivo (PubMed:17991826, PubMed:18775698). CC Involved in the regulation of fat mass, adipogenesis and body weight, CC thereby contributing to the regulation of body size and body fat CC accumulation (PubMed:19234441, PubMed:19680540, PubMed:21076408, CC PubMed:23817550, PubMed:23300482). Involved in the regulation of CC thermogenesis and the control of adipocyte differentiation into brown CC or white fat cells (PubMed:19234441, PubMed:19680540). Regulates CC activity of the dopaminergic midbrain circuitry via its ability to CC demethylate m6A in mRNAs (PubMed:23817550). CC {ECO:0000250|UniProtKB:Q9C0B1, ECO:0000269|PubMed:17991826, CC ECO:0000269|PubMed:18775698, ECO:0000269|PubMed:19234441, CC ECO:0000269|PubMed:19680540, ECO:0000269|PubMed:21076408, CC ECO:0000269|PubMed:23300482, ECO:0000269|PubMed:23817550, CC ECO:0000269|PubMed:28002401}. CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + a 5'-end (N(7)-methyl 5'- CC triphosphoguanosine)-(N(6),2'-O-dimethyladenosine) in mRNA + O2 = a CC 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in CC mRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:57896, CC Rhea:RHEA-COMP:11518, Rhea:RHEA-COMP:11519, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, CC ChEBI:CHEBI:30031, ChEBI:CHEBI:85958, ChEBI:CHEBI:85959; CC Evidence={ECO:0000250|UniProtKB:Q9C0B1}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + an N(6)-methyladenosine in mRNA + O2 = an CC adenosine in mRNA + CO2 + formaldehyde + succinate; CC Xref=Rhea:RHEA:49520, Rhea:RHEA-COMP:12414, Rhea:RHEA-COMP:12417, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, CC ChEBI:CHEBI:74449; EC=1.14.11.53; CC Evidence={ECO:0000305|PubMed:23817550}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + N(6)-methyladenosine in U6 snRNA + O2 = CC adenosine in U6 snRNA + CO2 + formaldehyde + succinate; CC Xref=Rhea:RHEA:57900, Rhea:RHEA-COMP:13573, Rhea:RHEA-COMP:13574, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, CC ChEBI:CHEBI:74449; Evidence={ECO:0000250|UniProtKB:Q9C0B1}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + a 5'-end (N(7)-methyl 5'- CC triphosphoguanosine)-(N(6),2'-O-dimethyladenosine) in U6 snRNA + O2 = CC a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) CC in U6 snRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:57904, CC Rhea:RHEA-COMP:15030, Rhea:RHEA-COMP:15031, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, CC ChEBI:CHEBI:30031, ChEBI:CHEBI:85958, ChEBI:CHEBI:85959; CC Evidence={ECO:0000250|UniProtKB:Q9C0B1}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + an N(1)-methyladenosine in tRNA + O2 = an CC adenosine in tRNA + CO2 + formaldehyde + succinate; CC Xref=Rhea:RHEA:54576, Rhea:RHEA-COMP:10242, Rhea:RHEA-COMP:12312, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, CC ChEBI:CHEBI:74491; Evidence={ECO:0000250|UniProtKB:Q9C0B1}; CC -!- COFACTOR: CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033; CC Evidence={ECO:0000269|PubMed:17991826}; CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269|PubMed:17991826}; CC -!- ACTIVITY REGULATION: Activated by ascorbate (PubMed:17991826). CC Inhibited by N-oxalylglycine, fumarate and succinate (PubMed:17991826). CC {ECO:0000269|PubMed:17991826}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC pH dependence: CC Optimum pH is 5.5-6. {ECO:0000269|PubMed:18775698}; CC -!- SUBUNIT: Monomer (PubMed:19680540). May also exist as homodimer CC (PubMed:19680540). {ECO:0000269|PubMed:19680540}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:17991826, CC ECO:0000269|PubMed:19234441, ECO:0000269|PubMed:19680540}. Nucleus CC speckle {ECO:0000250|UniProtKB:Q9C0B1}. Cytoplasm CC {ECO:0000250|UniProtKB:Q9C0B1}. Note=Localizes mainly in the nucleus, CC where it is able to demethylate N(6)-methyladenosine (m6A) and N(6),2'- CC O-dimethyladenosine cap (m6A(m)) in U6 small nuclear RNA (snRNA), N(1)- CC methyladenine from tRNAs and internal m6A in mRNAs. In the cytoplasm, CC mediates demethylation of m6A and m6A(m) in mRNAs and N(1)- CC methyladenine from tRNAs. {ECO:0000250|UniProtKB:Q9C0B1}. 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 Name=3; CC IsoId=Q8BGW1-3; Sequence=VSP_025009, VSP_025010; CC Name=4; CC IsoId=Q8BGW1-4; Sequence=VSP_025007, VSP_025008; CC -!- TISSUE SPECIFICITY: Ubiquitous. Detected in brain, brain cortex, CC hypothalamus, cerebellum, liver, pancreas, heart, kidney, white adipose CC tissue and skeletal muscle. Most abundant in the brain, particularly in CC hypothalamic nuclei governing energy balance. CC {ECO:0000269|PubMed:17991826, ECO:0000269|PubMed:19234441}. CC -!- INDUCTION: Down-regulated in fasting animals. CC {ECO:0000269|PubMed:17991826}. CC -!- DOMAIN: The 3D-structure of the Fe2OG dioxygenase domain is similar to CC that of the Fe2OG dioxygenase domain found in the bacterial DNA repair CC dioxygenase alkB and its mammalian orthologs, but sequence similarity CC is very low. As a consequence, the domain is not detected by protein CC signature databases. {ECO:0000250|UniProtKB:Q9C0B1}. CC -!- DISRUPTION PHENOTYPE: Elevated perinatal mortality (PubMed:19234441). CC Mice have normal body weight at birth, but show growth retardation from CC day 2 onwards, resulting in a weight reduction of 30-40% after 6 weeks, CC both in males and females (PubMed:19234441). In addition, animals CC display reduced nose to anus length (PubMed:19234441). Fat mass is CC reduced by 60% in males and by 23% in females (PubMed:19234441). Lean CC body mass is reduced by 26% in males and 19% in females CC (PubMed:19234441). White adipose tissue decreases more and more over CC time, while brown adipose tissue is not affected (PubMed:19234441). CC Serum leptin levels are decreased, while serum levels of adiponectin CC are increased (PubMed:19234441). Mice exhibit significant hyperphagia CC after correction for body weight (PubMed:19234441). They show increased CC oxygen consumption, carbon dioxide production and heat generation, CC indicating increased energy expenditure, in spite of reduced CC spontaneous locomotor activity (PubMed:19234441). Plasma adrenaline CC concentrations are significantly increased (PubMed:19234441). Overall CC glucose metabolism appears normal (PubMed:19234441). Conditional CC deletion in the adult affects body composition and metabolism, and CC causes a small reduction in food intake and weight gain CC (PubMed:23300482). Mice with conditional deletion in dopaminergic CC neurons show abnormal dopamine signaling pathways, including impaired CC dopamine receptor type 2 (D2R) and type 3 (D3R) signaling and the CC related locomotion function (PubMed:23817550). Deficient mice show CC increased N(6)-methyladenosine (m6A) in a subset of mRNAs important for CC neuronal signaling, including many in the dopaminergic signaling CC pathway (PubMed:23817550). Knockout cells show strongly increased CC levels of N(6),2'-O-dimethyladenosine cap (m6A(m)) mRNAs CC (PubMed:28002401). {ECO:0000269|PubMed:19234441, CC ECO:0000269|PubMed:23300482, ECO:0000269|PubMed:23817550, CC ECO:0000269|PubMed:28002401}. CC -!- SIMILARITY: Belongs to the fto family. {ECO:0000305}. CC -!- CAUTION: Many publications have reported a critical role of Fto in CC regulating fat mass, adipogenesis and total body weight CC (PubMed:19234441, PubMed:19680540, PubMed:21076408, PubMed:23817550, CC PubMed:23300482). However, some reports suggest that some effects are CC indirect and caused by impaired expression of adjacent genes such as CC Irx3 and Rpgrip1l (PubMed:24807221, PubMed:24646999). CC {ECO:0000269|PubMed:19234441, ECO:0000269|PubMed:19680540, CC ECO:0000269|PubMed:21076408, ECO:0000269|PubMed:23300482, CC ECO:0000269|PubMed:23817550, ECO:0000269|PubMed:24646999, CC ECO:0000269|PubMed:24807221}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC98247.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) 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 CCDS; CCDS22521.1; -. [Q8BGW1-1] DR RefSeq; NP_036066.2; NM_011936.2. [Q8BGW1-1] DR AlphaFoldDB; Q8BGW1; -. DR SMR; Q8BGW1; -. DR BioGRID; 204941; 21. DR STRING; 10090.ENSMUSP00000068380; -. DR ChEMBL; CHEMBL3611964; -. DR GlyGen; Q8BGW1; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q8BGW1; -. DR PhosphoSitePlus; Q8BGW1; -. DR SwissPalm; Q8BGW1; -. DR EPD; Q8BGW1; -. DR MaxQB; Q8BGW1; -. DR PaxDb; 10090-ENSMUSP00000068380; -. DR PeptideAtlas; Q8BGW1; -. DR ProteomicsDB; 266879; -. [Q8BGW1-1] DR ProteomicsDB; 266880; -. [Q8BGW1-2] DR ProteomicsDB; 266881; -. [Q8BGW1-3] DR ProteomicsDB; 266882; -. [Q8BGW1-4] DR Pumba; Q8BGW1; -. DR Antibodypedia; 28448; 511 antibodies from 43 providers. DR DNASU; 26383; -. DR Ensembl; ENSMUST00000069718.15; ENSMUSP00000068380.8; ENSMUSG00000055932.16. [Q8BGW1-1] DR Ensembl; ENSMUST00000125471.8; ENSMUSP00000147563.2; ENSMUSG00000055932.16. [Q8BGW1-4] DR Ensembl; ENSMUST00000128081.8; ENSMUSP00000147548.2; ENSMUSG00000055932.16. [Q8BGW1-2] DR Ensembl; ENSMUST00000136802.8; ENSMUSP00000147603.2; ENSMUSG00000055932.16. [Q8BGW1-3] DR GeneID; 26383; -. DR KEGG; mmu:26383; -. DR UCSC; uc009msq.2; mouse. [Q8BGW1-4] DR UCSC; uc009msr.2; mouse. [Q8BGW1-3] DR UCSC; uc009mss.2; mouse. [Q8BGW1-2] DR UCSC; uc009mst.2; mouse. [Q8BGW1-1] DR AGR; MGI:1347093; -. DR CTD; 79068; -. DR MGI; MGI:1347093; Fto. DR VEuPathDB; HostDB:ENSMUSG00000055932; -. DR eggNOG; ENOG502QR31; Eukaryota. DR GeneTree; ENSGT00390000017730; -. DR HOGENOM; CLU_041676_0_0_1; -. DR InParanoid; Q8BGW1; -. DR OMA; NYSCEGS; -. DR OrthoDB; 5396564at2759; -. DR PhylomeDB; Q8BGW1; -. DR TreeFam; TF333296; -. DR BRENDA; 1.14.11.53; 3474. DR Reactome; R-MMU-73943; Reversal of alkylation damage by DNA dioxygenases. DR BioGRID-ORCS; 26383; 6 hits in 114 CRISPR screens. DR ChiTaRS; Fto; mouse. DR PRO; PR:Q8BGW1; -. DR Proteomes; UP000000589; Chromosome 8. DR RNAct; Q8BGW1; Protein. DR Bgee; ENSMUSG00000055932; Expressed in undifferentiated genital tubercle and 251 other cell types or tissues. DR ExpressionAtlas; Q8BGW1; baseline and differential. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI. DR GO; GO:0016607; C:nuclear speck; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; ISO:MGI. 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:1990931; F:mRNA N6-methyladenosine dioxygenase activity; 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:1990984; F:tRNA demethylase activity; ISS:UniProtKB. DR GO; GO:0060612; P:adipose tissue development; IMP:UniProtKB. DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; IDA:BHF-UCL. DR GO; GO:0080111; P:DNA demethylation; IDA:BHF-UCL. DR GO; GO:0061157; P:mRNA destabilization; ISS:UniProtKB. DR GO; GO:1903999; P:negative regulation of eating behavior; ISO:MGI. DR GO; GO:0001649; P:osteoblast differentiation; ISO:MGI. DR GO; GO:0070989; P:oxidative demethylation; IDA:BHF-UCL. 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:0043065; P:positive regulation of apoptotic process; ISO:MGI. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; ISO:MGI. DR GO; GO:0090335; P:regulation of brown fat cell differentiation; ISO:MGI. DR GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; ISO:MGI. 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:0019233; P:sensory perception of pain; ISO:MGI. DR GO; GO:0001659; P:temperature homeostasis; IMP:UniProtKB. DR Gene3D; 2.60.120.590; Alpha-ketoglutarate-dependent dioxygenase AlkB-like; 1. DR Gene3D; 1.20.58.1470; FTO C-terminal domain; 1. DR InterPro; IPR037151; AlkB-like_sf. DR InterPro; IPR032868; FTO. DR InterPro; IPR024366; FTO_C. DR InterPro; IPR038413; FTO_C_sf. DR InterPro; IPR024367; FTO_cat_dom. DR PANTHER; PTHR31291; ALPHA-KETOGLUTARATE-DEPENDENT DIOXYGENASE FTO; 1. DR PANTHER; PTHR31291:SF2; ALPHA-KETOGLUTARATE-DEPENDENT DIOXYGENASE FTO; 1. DR Pfam; PF12934; FTO_CTD; 1. DR Pfam; PF12933; FTO_NTD; 1. DR SMART; SM01223; FTO_NTD; 1. DR Genevisible; Q8BGW1; MM. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; Cytoplasm; Dioxygenase; Iron; KW Metal-binding; Nucleus; Oxidoreductase; Reference proteome. FT CHAIN 1..502 FT /note="Alpha-ketoglutarate-dependent dioxygenase FTO" FT /id="PRO_0000286164" FT REGION 32..324 FT /note="Fe2OG dioxygenase domain" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT REGION 210..221 FT /note="Loop L1; predicted to block binding of double- FT stranded DNA or RNA" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 96 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 108 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 202 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 228..231 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 228 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 230 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 292 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 304 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 313..315 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 317 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT BINDING 319 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT MOD_RES 213 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9C0B1" FT VAR_SEQ 296..316 FT /note="DDLNATHQHCVLAGSQPRFSS -> GNVGSLRVGHLWGFEIHFWIL (in FT isoform 4)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_025007" FT VAR_SEQ 317..502 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_025008" FT VAR_SEQ 411..413 FT /note="TNA -> VSA (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_025009" FT VAR_SEQ 414..502 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_025010" FT VAR_SEQ 453..502 FT /note="CQSRVVRTLPVQQKPDCRPYWEKDDPSMPLPFDLTDVVSELRGQLLEARS FT -> FVLLRGGVWCPCPSSARPAQRTKVEDILS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14621295" FT /id="VSP_025011" FT MUTAGEN 304 FT /note="H->A: Reduced enzyme activity." FT /evidence="ECO:0000269|PubMed:17991826" FT MUTAGEN 313 FT /note="R->A: Loss of enzyme activity." FT /evidence="ECO:0000269|PubMed:17991826" FT MUTAGEN 367 FT /note="I->A: Reduces enzyme activity by about 60%." FT /evidence="ECO:0000269|PubMed:19680540" FT MUTAGEN 367 FT /note="I->F: Alters protein structure and causes an FT increase in whole body metabolism, leading to a lean FT phenotype in adult males, but not in females." FT /evidence="ECO:0000269|PubMed:19680540" FT CONFLICT 181 FT /note="G -> R (in Ref. 3; BAC32382)" FT /evidence="ECO:0000305" FT CONFLICT 384 FT /note="N -> S (in Ref. 1; CAB59324, 2; BAC98247, 3; FT BAC40629 and 4; AAH22222)" FT /evidence="ECO:0000305" FT CONFLICT 410 FT /note="M -> V (in Ref. 2; BAC98247, 3; BAC40629 and 4; FT AAH22222)" FT /evidence="ECO:0000305" FT CONFLICT 463 FT /note="V -> A (in Ref. 3; BAC40629 and 4; AAH22222)" FT /evidence="ECO:0000305" 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 //