FTO_MOUSE
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 03-AUG-2022, entry version 133.
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};
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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 iPTMnet; Q8BGW1; -.
DR PhosphoSitePlus; Q8BGW1; -.
DR EPD; Q8BGW1; -.
DR MaxQB; Q8BGW1; -.
DR PaxDb; Q8BGW1; -.
DR PeptideAtlas; Q8BGW1; -.
DR PRIDE; Q8BGW1; -.
DR ProteomicsDB; 266879; -. [Q8BGW1-1]
DR ProteomicsDB; 266880; -. [Q8BGW1-2]
DR ProteomicsDB; 266881; -. [Q8BGW1-3]
DR ProteomicsDB; 266882; -. [Q8BGW1-4]
DR Antibodypedia; 28448; 457 antibodies from 43 providers.
DR DNASU; 26383; -.
DR Ensembl; ENSMUST00000069718; ENSMUSP00000068380; ENSMUSG00000055932. [Q8BGW1-1]
DR Ensembl; ENSMUST00000125471; ENSMUSP00000147563; ENSMUSG00000055932. [Q8BGW1-4]
DR Ensembl; ENSMUST00000128081; ENSMUSP00000147548; ENSMUSG00000055932. [Q8BGW1-2]
DR Ensembl; ENSMUST00000136802; ENSMUSP00000147603; ENSMUSG00000055932. [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 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; GEKACWR; -.
DR OrthoDB; 1300974at2759; -.
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 109 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 248 other tissues.
DR ExpressionAtlas; Q8BGW1; baseline and differential.
DR Genevisible; Q8BGW1; MM.
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: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:0090335; P:regulation of brown fat cell differentiation; 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:0001659; P:temperature homeostasis; IMP:UniProtKB.
DR Gene3D; 1.20.58.1470; -; 1.
DR Gene3D; 2.60.120.590; -; 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; PTHR31291; 1.
DR Pfam; PF12934; FTO_CTD; 1.
DR Pfam; PF12933; FTO_NTD; 1.
DR SMART; SM01223; FTO_NTD; 1.
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
