FTO_HUMAN
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 03-AUG-2022, entry version 147.
DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO {ECO:0000305};
DE AltName: Full=Fat mass and obesity-associated protein {ECO:0000303|PubMed:17496892};
DE AltName: Full=U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO {ECO:0000305};
DE EC=1.14.11.- {ECO:0000269|PubMed:30197295};
DE AltName: Full=U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO {ECO:0000305};
DE EC=1.14.11.- {ECO:0000269|PubMed:30197295};
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:0000269|PubMed:28002401, ECO:0000269|PubMed:30197295};
DE AltName: Full=mRNA N(6)-methyladenosine demethylase FTO {ECO:0000305};
DE EC=1.14.11.53 {ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:30197295, ECO:0000305|PubMed:22002720};
DE AltName: Full=tRNA N1-methyl adenine demethylase FTO {ECO:0000305};
DE EC=1.14.11.- {ECO:0000269|PubMed:30197295};
GN Name=FTO {ECO:0000303|PubMed:17496892, ECO:0000312|HGNC:HGNC:24678};
GN Synonyms=KIAA1752 {ECO:0000303|PubMed:11214970};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX 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. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT 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., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., 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., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., 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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP POLYMORPHISM, 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., Marre M.,
RA 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 POLYMORPHISM, 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., Shields B.,
RA Harries L.W., Barrett J.C., Ellard S., Groves C.J., Knight B., Patch A.M.,
RA Ness A.R., Ebrahim S., Lawlor D.A., Ring S.M., Ben-Shlomo Y.,
RA Jarvelin M.-R., Sovio U., Bennett A.J., Melzer D., Ferrucci L., Loos R.J.,
RA Barroso I., Wareham N.J., Karpe F., Owen K.R., Cardon L.R., Walker M.,
RA Hitman G.A., Palmer C.N., Doney A.S., Morris A.D., Davey-Smith G.,
RA Hattersley A.T., McCarthy M.I.;
RT "A common variant in the FTO gene is associated with body mass index and
RT 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 single-
RT 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 IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
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., Buerckstuemmer T.,
RA 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 FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF 231-HIS--ASP-233, AND
RP CHARACTERIZATION OF VARIANT GDFD GLN-316.
RX PubMed=22002720; DOI=10.1038/nchembio.687;
RA Jia G., Fu Y., Zhao X., Dai Q., Zheng G., Yang Y., Yi C., Lindahl T.,
RA Pan T., Yang Y.G., He C.;
RT "N6-methyladenosine in nuclear RNA is a major substrate of the obesity-
RT associated FTO.";
RL Nat. Chem. Biol. 7:885-887(2011).
RN [10]
RP POLYMORPHISM, AND INVOLVEMENT IN BMIQ14.
RX PubMed=22982992; DOI=10.1038/nature11401;
RA Yang J., Loos R.J., Powell J.E., Medland S.E., Speliotes E.K.,
RA Chasman D.I., Rose L.M., Thorleifsson G., Steinthorsdottir V., Maegi R.,
RA Waite L., Smith A.V., Yerges-Armstrong L.M., Monda K.L., Hadley D.,
RA Mahajan A., Li G., Kapur K., Vitart V., Huffman J.E., Wang S.R., Palmer C.,
RA Esko T., Fischer K., Zhao J.H., Demirkan A., Isaacs A., Feitosa M.F.,
RA Luan J., Heard-Costa N.L., White C., Jackson A.U., Preuss M., Ziegler A.,
RA Eriksson J., Kutalik Z., Frau F., Nolte I.M., Van Vliet-Ostaptchouk J.V.,
RA Hottenga J.J., Jacobs K.B., Verweij N., Goel A., Medina-Gomez C.,
RA Estrada K., Bragg-Gresham J.L., Sanna S., Sidore C., Tyrer J., Teumer A.,
RA Prokopenko I., Mangino M., Lindgren C.M., Assimes T.L., Shuldiner A.R.,
RA Hui J., Beilby J.P., McArdle W.L., Hall P., Haritunians T., Zgaga L.,
RA Kolcic I., Polasek O., Zemunik T., Oostra B.A., Junttila M.J.,
RA Groenberg H., Schreiber S., Peters A., Hicks A.A., Stephens J., Foad N.S.,
RA Laitinen J., Pouta A., Kaakinen M., Willemsen G., Vink J.M., Wild S.H.,
RA Navis G., Asselbergs F.W., Homuth G., John U., Iribarren C., Harris T.,
RA Launer L., Gudnason V., O'Connell J.R., Boerwinkle E., Cadby G.,
RA Palmer L.J., James A.L., Musk A.W., Ingelsson E., Psaty B.M.,
RA Beckmann J.S., Waeber G., Vollenweider P., Hayward C., Wright A.F.,
RA Rudan I., Groop L.C., Metspalu A., Khaw K.T., van Duijn C.M., Borecki I.B.,
RA Province M.A., Wareham N.J., Tardif J.C., Huikuri H.V., Cupples L.A.,
RA Atwood L.D., Fox C.S., Boehnke M., Collins F.S., Mohlke K.L., Erdmann J.,
RA Schunkert H., Hengstenberg C., Stark K., Lorentzon M., Ohlsson C., Cusi D.,
RA Staessen J.A., Van der Klauw M.M., Pramstaller P.P., Kathiresan S.,
RA Jolley J.D., Ripatti S., Jarvelin M.R., de Geus E.J., Boomsma D.I.,
RA Penninx B., Wilson J.F., Campbell H., Chanock S.J., van der Harst P.,
RA Hamsten A., Watkins H., Hofman A., Witteman J.C., Zillikens M.C.,
RA Uitterlinden A.G., Rivadeneira F., Zillikens M.C., Kiemeney L.A.,
RA Vermeulen S.H., Abecasis G.R., Schlessinger D., Schipf S., Stumvoll M.,
RA Toenjes A., Spector T.D., North K.E., Lettre G., McCarthy M.I.,
RA Berndt S.I., Heath A.C., Madden P.A., Nyholt D.R., Montgomery G.W.,
RA Martin N.G., McKnight B., Strachan D.P., Hill W.G., Snieder H.,
RA Ridker P.M., Thorsteinsdottir U., Stefansson K., Frayling T.M.,
RA Hirschhorn J.N., Goddard M.E., Visscher P.M.;
RT "FTO genotype is associated with phenotypic variability of body mass
RT index.";
RL Nature 490:267-272(2012).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-4, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [12]
RP INVOLVEMENT IN OBESITY.
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 INVOLVEMENT IN OBESITY.
RX PubMed=26287746; DOI=10.1056/nejmoa1502214;
RA Claussnitzer M., Dankel S.N., Kim K.H., Quon G., Meuleman W., Haugen C.,
RA Glunk V., Sousa I.S., Beaudry J.L., Puviindran V., Abdennur N.A., Liu J.,
RA Svensson P.A., Hsu Y.H., Drucker D.J., Mellgren G., Hui C.C., Hauner H.,
RA Kellis M.;
RT "FTO obesity variant circuitry and adipocyte browning in humans.";
RL N. Engl. J. Med. 373:895-907(2015).
RN [14]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=26458103; DOI=10.1038/nature15377;
RA Zhou J., Wan J., Gao X., Zhang X., Jaffrey S.R., Qian S.B.;
RT "Dynamic m(6)A mRNA methylation directs translational control of heat shock
RT response.";
RL Nature 526:591-594(2015).
RN [15]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=28017614; DOI=10.1016/j.ccell.2016.11.017;
RA Li Z., Weng H., Su R., Weng X., Zuo Z., Li C., Huang H., Nachtergaele S.,
RA Dong L., Hu C., Qin X., Tang L., Wang Y., Hong G.M., Huang H., Wang X.,
RA Chen P., Gurbuxani S., Arnovitz S., Li Y., Li S., Strong J., Neilly M.B.,
RA Larson R.A., Jiang X., Zhang P., Jin J., He C., Chen J.;
RT "FTO plays an oncogenic role in acute myeloid leukemia as a N6-
RT methyladenosine RNA demethylase.";
RL Cancer Cell 31:127-141(2017).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP SUBCELLULAR LOCATION.
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).
RN [17]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=29249359; DOI=10.1016/j.cell.2017.11.031;
RA Su R., Dong L., Li C., Nachtergaele S., Wunderlich M., Qing Y., Deng X.,
RA Wang Y., Weng X., Hu C., Yu M., Skibbe J., Dai Q., Zou D., Wu T., Yu K.,
RA Weng H., Huang H., Ferchen K., Qin X., Zhang B., Qi J., Sasaki A.T.,
RA Plas D.R., Bradner J.E., Wei M., Marcucci G., Jiang X., Mulloy J.C.,
RA Jin J., He C., Chen J.;
RT "R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA
RT signaling.";
RL Cell 172:90-105(2018).
RN [18]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=30197295; DOI=10.1016/j.molcel.2018.08.011;
RA Wei J., Liu F., Lu Z., Fei Q., Ai Y., He P.C., Shi H., Cui X., Su R.,
RA Klungland A., Jia G., Chen J., He C.;
RT "Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell
RT nucleus and cytoplasm.";
RL Mol. Cell 71:973-985(2018).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 32-505 IN COMPLEX WITH IRON IONS;
RP N-OXALYLGLYCINE AND 3-METHYLTHYMIDINE, CATALYTIC ACTIVITY, FUNCTION,
RP COFACTOR, ACTIVITY REGULATION, MUTAGENESIS OF ARG-96; TYR-108; PHE-114;
RP 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 [20] {ECO:0007744|PDB:4IDZ, ECO:0007744|PDB:4IE0, ECO:0007744|PDB:4IE4, ECO:0007744|PDB:4IE5, ECO:0007744|PDB:4IE6, ECO:0007744|PDB:4IE7}
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 32-505 IN COMPLEX WITH ZINC.
RX PubMed=23547775; DOI=10.1021/jm400193d;
RA Aik W., Demetriades M., Hamdan M.K., Bagg E.A., Yeoh K.K., Lejeune C.,
RA Zhang Z., McDonough M.A., Schofield C.J.;
RT "Structural basis for inhibition of the fat mass and obesity associated
RT protein (FTO).";
RL J. Med. Chem. 56:3680-3688(2013).
RN [21] {ECO:0007744|PDB:4CXW, ECO:0007744|PDB:4CXX, ECO:0007744|PDB:4CXY}
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 32-505 IN COMPLEX WITH ZINC,
RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=28553460; DOI=10.1039/c4sc02554g;
RA Toh J.D.W., Sun L., Lau L.Z.M., Tan J., Low J.J.A., Tang C.W.Q.,
RA Cheong E.J.Y., Tan M.J.H., Chen Y., Hong W., Gao Y.G., Woon E.C.Y.;
RT "A strategy based on nucleotide specificity leads to a subfamily-selective
RT and cell-active inhibitor of N6-methyladenosine demethylase FTO.";
RL Chem. Sci. 6:112-122(2015).
RN [22] {ECO:0007744|PDB:4ZS2, ECO:0007744|PDB:4ZS3}
RP X-RAY CRYSTALLOGRAPHY (2.16 ANGSTROMS) OF 32-505 IN COMPLEX WITH
RP 2-OXOGLUTARATE AND MANGANESE, FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY
RP REGULATION.
RX PubMed=26457839; DOI=10.1021/jacs.5b06690;
RA Wang T., Hong T., Huang Y., Su H., Wu F., Chen Y., Wei L., Huang W.,
RA Hua X., Xia Y., Xu J., Gan J., Yuan B., Feng Y., Zhang X., Yang C.G.,
RA Zhou X.;
RT "Fluorescein derivatives as bifunctional molecules for the simultaneous
RT inhibiting and labeling of FTO protein.";
RL J. Am. Chem. Soc. 137:13736-13739(2015).
RN [23] {ECO:0007744|PDB:4QKN}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 32-503 IN COMPLEX WITH MANGANESE
RP AND N-OXALYLGLYCINE, FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=25452335; DOI=10.1093/nar/gku1276;
RA Huang Y., Yan J., Li Q., Li J., Gong S., Zhou H., Gan J., Jiang H.,
RA Jia G.F., Luo C., Yang C.G.;
RT "Meclofenamic acid selectively inhibits FTO demethylation of m6A over
RT ALKBH5.";
RL Nucleic Acids Res. 43:373-384(2015).
RN [24]
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., Yeo G.S.,
RA Meyre D., Golzio C., Molinari F., Kadhom N., Etchevers H.C., Saudek V.,
RA Farooqi I.S., Froguel P., Lindahl T., O'Rahilly S., Munnich A.,
RA 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).
RN [25]
RP VARIANT GDFD GLN-322.
RX PubMed=26697951; DOI=10.1002/ajmg.a.37515;
RA Rohena L., Lawson M., Guzman E., Ganapathi M., Cho M.T., Haverfield E.,
RA Anyane-Yeboa K.;
RT "FTO variant associated with malformation syndrome.";
RL Am. J. Med. Genet. A 170:1023-1028(2016).
RN [26]
RP VARIANT PRO-271.
RX PubMed=26740239; DOI=10.1038/jhg.2015.160;
RA Caglayan A.O., Tueysuez B., Coskun S., Quon J., Harmanci A.S.,
RA Baranoski J.F., Baran B., Erson-Omay E.Z., Henegariu O., Mane S.M.,
RA Bilguevar K., Yasuno K., Guenel M.;
RT "A patient with a novel homozygous missense mutation in FTO and concomitant
RT nonsense mutation in CETP.";
RL J. Hum. Genet. 61:395-403(2016).
RN [27]
RP VARIANT GDFD PHE-319, AND CHARACTERIZATION OF VARIANT GDFD PHE-319.
RX PubMed=26378117; DOI=10.1136/jmedgenet-2015-103399;
RA Daoud H., Zhang D., McMurray F., Yu A., Luco S.M., Vanstone J.,
RA Jarinova O., Carson N., Wickens J., Shishodia S., Choi H., McDonough M.A.,
RA Schofield C.J., Harper M.E., Dyment D.A., Armour C.M.;
RT "Identification of a pathogenic FTO mutation by next-generation sequencing
RT in a newborn with growth retardation and developmental delay.";
RL J. Med. Genet. 53:200-207(2016).
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:22002720, PubMed:26458103, PubMed:28002401, PubMed:30197295,
CC PubMed:26457839, PubMed:25452335). Specifically demethylates N(6)-
CC methyladenosine (m6A) RNA, the most prevalent internal modification of
CC messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720,
CC PubMed:26458103, PubMed:30197295, PubMed:26457839, PubMed:25452335).
CC M6A demethylation by FTO affects mRNA expression and stability
CC (PubMed:30197295). Also able to demethylate m6A in U6 small nuclear RNA
CC (snRNA) (PubMed:30197295). Mediates demethylation of N(6),2'-O-
CC dimethyladenosine cap (m6A(m)), by demethylating the N(6)-
CC methyladenosine at the second transcribed position of mRNAs and U6
CC snRNA (PubMed:28002401, PubMed:30197295). Demethylation of m6A(m) in
CC the 5'-cap by FTO affects mRNA stability by promoting susceptibility to
CC decapping (PubMed:28002401). Also acts as a tRNA demethylase by
CC removing N(1)-methyladenine from various tRNAs (PubMed:30197295). Has
CC no activity towards 1-methylguanine (PubMed:20376003). Has no
CC detectable activity towards double-stranded DNA (PubMed:20376003). Also
CC able to repair alkylated DNA and RNA by oxidative demethylation:
CC demethylates single-stranded RNA containing 3-methyluracil, single-
CC stranded DNA containing 3-methylthymine and has low demethylase
CC activity towards single-stranded DNA containing 1-methyladenine or 3-
CC methylcytosine (PubMed:18775698, PubMed:20376003). Ability to repair
CC alkylated DNA and RNA is however unsure in vivo (PubMed:18775698,
CC PubMed:20376003). Involved in the regulation of fat mass, adipogenesis
CC and body weight, thereby contributing to the regulation of body size
CC and body fat accumulation (PubMed:18775698, PubMed:20376003). Involved
CC in the regulation of thermogenesis and the control of adipocyte
CC differentiation into brown or white fat cells (PubMed:26287746).
CC Regulates activity of the dopaminergic midbrain circuitry via its
CC ability to demethylate m6A in mRNAs (By similarity). Plays an oncogenic
CC role in a number of acute myeloid leukemias by enhancing leukemic
CC oncogene-mediated cell transformation: acts by mediating m6A
CC demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA,
CC leading to promote their expression (PubMed:28017614, PubMed:29249359).
CC {ECO:0000250|UniProtKB:Q8BGW1, ECO:0000269|PubMed:18775698,
CC ECO:0000269|PubMed:20376003, ECO:0000269|PubMed:22002720,
CC ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26287746,
CC ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:26458103,
CC ECO:0000269|PubMed:28002401, ECO:0000269|PubMed:28017614,
CC ECO:0000269|PubMed:29249359, ECO:0000269|PubMed:30197295}.
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:0000269|PubMed:28002401, ECO:0000269|PubMed:30197295};
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:0000269|PubMed:25452335, ECO:0000269|PubMed:26457839,
CC ECO:0000269|PubMed:30197295, ECO:0000305|PubMed:22002720};
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:0000269|PubMed:30197295};
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:0000269|PubMed:30197295};
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:0000269|PubMed:30197295};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000269|PubMed:20376003};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269|PubMed:20376003};
CC -!- ACTIVITY REGULATION: Activated by ascorbate (By similarity). Inhibited
CC by N-oxalylglycine, fumarate and succinate (By similarity). RNA N(6)-
CC methyladenosine demethylase activity is inhibited by fluorescein
CC derivatives (PubMed:26457839). RNA N(6)-methyladenosine demethylase
CC activity is selectively inhibited by meclofenamic acid; inhibition is
CC specific to FTO and meclofenamic acid does not inhibit ALKBH5
CC (PubMed:25452335). Specifically inhibited by R-2-hydroxyglutarate (R-
CC 2HG), an oncometabolite that also exerts a broad antileukemic activity
CC (PubMed:29249359). Inhibition by R-2HG leads to increased level of
CC N(6)-methyladenosine-containing transcripts, leading to down-regulate
CC expression of MYC and CEBPA transcripts (PubMed:29249359).
CC {ECO:0000250|UniProtKB:Q8BGW1, ECO:0000269|PubMed:25452335,
CC ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:29249359}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.34 uM for m(7)Gppp(m6A(m))CA mRNA {ECO:0000269|PubMed:28002401};
CC KM=16.09 uM for m(7)Gppp(m6ACA mRNA {ECO:0000269|PubMed:28002401};
CC KM=9.29 uM for GG(m6A)CU mRNA {ECO:0000269|PubMed:28002401};
CC KM=6.4 uM for m(7)GpppAC(m6) mRNA {ECO:0000269|PubMed:28002401};
CC Note=kcat is 8.78 min(-1) for m(7)Gppp(m6A(m))CA mRNA. kcat is 7.77
CC min(-1) for m(7)Gppp(m6A)CA mRNA. kcat is 0.54 min(-1) for GG(m6A)CU
CC mRNA. kcat is 0.46 min(-1) for m(7)GpppAC(m6) mRNA.
CC {ECO:0000269|PubMed:28002401};
CC pH dependence:
CC Optimum pH is 5.5-6. {ECO:0000269|PubMed:18775698};
CC -!- SUBUNIT: Monomer (By similarity). May also exist as homodimer (By
CC similarity). {ECO:0000250|UniProtKB:Q8BGW1}.
CC -!- INTERACTION:
CC Q9C0B1-2; X5D778: ANKRD11; NbExp=3; IntAct=EBI-18138793, EBI-17183751;
CC Q9C0B1-2; Q9NX04: C1orf109; NbExp=3; IntAct=EBI-18138793, EBI-8643161;
CC Q9C0B1-2; Q2TAC2-2: CCDC57; NbExp=3; IntAct=EBI-18138793, EBI-10961624;
CC Q9C0B1-2; Q92989: CLP1; NbExp=3; IntAct=EBI-18138793, EBI-2559831;
CC Q9C0B1-2; Q86UW9: DTX2; NbExp=3; IntAct=EBI-18138793, EBI-740376;
CC Q9C0B1-2; O95967: EFEMP2; NbExp=3; IntAct=EBI-18138793, EBI-743414;
CC Q9C0B1-2; Q9P2W3: GNG13; NbExp=3; IntAct=EBI-18138793, EBI-11427343;
CC Q9C0B1-2; O95872: GPANK1; NbExp=3; IntAct=EBI-18138793, EBI-751540;
CC Q9C0B1-2; Q14005-2: IL16; NbExp=3; IntAct=EBI-18138793, EBI-17178971;
CC Q9C0B1-2; Q2WGJ6: KLHL38; NbExp=3; IntAct=EBI-18138793, EBI-6426443;
CC Q9C0B1-2; Q9UI95: MAD2L2; NbExp=3; IntAct=EBI-18138793, EBI-77889;
CC Q9C0B1-2; Q6PF18: MORN3; NbExp=3; IntAct=EBI-18138793, EBI-9675802;
CC Q9C0B1-2; Q9UBU9: NXF1; NbExp=3; IntAct=EBI-18138793, EBI-398874;
CC Q9C0B1-2; Q9NQX0: PRDM6; NbExp=3; IntAct=EBI-18138793, EBI-11320284;
CC Q9C0B1-2; Q92529: SHC3; NbExp=3; IntAct=EBI-18138793, EBI-79084;
CC Q9C0B1-2; O14787-2: TNPO2; NbExp=3; IntAct=EBI-18138793, EBI-12076664;
CC Q9C0B1-2; Q6DKK2: TTC19; NbExp=3; IntAct=EBI-18138793, EBI-948354;
CC Q9C0B1-2; A0A024R8A9: USP20; NbExp=3; IntAct=EBI-18138793, EBI-14096082;
CC Q9C0B1-2; Q15935: ZNF77; NbExp=3; IntAct=EBI-18138793, EBI-12840750;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:22002720,
CC ECO:0000269|PubMed:26458103, ECO:0000269|PubMed:28002401,
CC ECO:0000269|PubMed:30197295}. Nucleus speckle
CC {ECO:0000269|PubMed:22002720}. Cytoplasm {ECO:0000269|PubMed:30197295}.
CC Note=Localizes mainly in the nucleus, where it is able to demethylate
CC N(6)-methyladenosine (m6A) and N(6),2'-O-dimethyladenosine cap (m6A(m))
CC in U6 small nuclear RNA (snRNA), N(1)-methyladenine from tRNAs and
CC internal m6A in mRNAs (PubMed:30197295). In the cytoplasm, mediates
CC demethylation of m6A and m6A(m) in mRNAs and N(1)-methyladenine from
CC tRNAs (PubMed:30197295). {ECO:0000269|PubMed:30197295}.
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 Name=3;
CC IsoId=Q9C0B1-3; Sequence=VSP_025002, VSP_025006;
CC Name=4;
CC IsoId=Q9C0B1-4; Sequence=VSP_025003;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with relatively high
CC expression in adrenal glands and brain; especially in hypothalamus and
CC pituitary (PubMed:17434869, PubMed:17496892). Highly expressed in
CC highly expressed in acute myeloid leukemias (AML) with t(11;11)(q23;23)
CC with KMT2A/MLL1 rearrangements, t(15;17)(q21;q21)/PML-RARA, FLT3-ITD,
CC and/or NPM1 mutations (PubMed:28017614). {ECO:0000269|PubMed:17434869,
CC ECO:0000269|PubMed:17496892, ECO:0000269|PubMed:28017614}.
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:0000269|PubMed:20376003}.
CC -!- POLYMORPHISM: Genetic variations at the FTO locus define the body mass
CC index quantitative trait locus 14 (BMIQ14) [MIM:612460]. Variance in
CC body mass index is a susceptibility factor for obesity.
CC {ECO:0000269|PubMed:17434869, ECO:0000269|PubMed:17496892,
CC ECO:0000269|PubMed:22982992}.
CC -!- DISEASE: Growth retardation, developmental delay, and facial
CC dysmorphism (GDFD) [MIM:612938]: A severe polymalformation syndrome
CC characterized by postnatal growth retardation, microcephaly, severe
CC psychomotor delay, functional brain deficits and characteristic facial
CC dysmorphism. In some patients, structural brain malformations, cardiac
CC defects, genital anomalies, and cleft palate are observed. Early death
CC occurs by the age of 3 years. {ECO:0000269|PubMed:19559399,
CC ECO:0000269|PubMed:22002720, ECO:0000269|PubMed:26378117,
CC ECO:0000269|PubMed:26697951}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by
CC an increase of body weight beyond the limitation of skeletal and
CC physical requirements, as the result of excessive accumulation of body
CC fat. {ECO:0000269|PubMed:24646999, ECO:0000269|PubMed:26287746}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry. It is unclear whether variations
CC associated with obesity directly affect FTO function or alter the
CC expression of adjacent genes such as IRX3, rather than FTO itself
CC (PubMed:24646999, PubMed:26287746). A pathogenic intronic FTO variation
CC (rs1421085) disrupts an evolutionarily conserved motif for ARID5B
CC binding (PubMed:26287746). Loss of ARID5B binding results in
CC overexpression of two genes distal to FTO, IRX3 and IRX5. IRX3 and IRX5
CC overexpression shifts pre-adipocytes differentiation from brown to
CC white fat cells, resulting in increased lipid storage and loss of
CC mitochondrial thermogenesis (PubMed:26287746).
CC {ECO:0000269|PubMed:24646999, ECO:0000269|PubMed:26287746}.
CC -!- SIMILARITY: Belongs to the fto family. {ECO:0000305}.
CC -!- CAUTION: According to a report, mainly mediates demethylation of
CC N(6),2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N(6)-
CC methyladenosine adjacent to mRNA cap, whereas it has low activity
CC toward internal N(6)-methyladenosine (m6A) in mRNAs (PubMed:28002401).
CC According to a second report, has strong activity toward internal N(6)-
CC methyladenosine (m6A) in mRNAs and is able to demethylate different RNA
CC species, such as tRNA, mRNA or small nuclear RNA (snRNA), depending on
CC the context and subcellular location (PubMed:30197295).
CC {ECO:0000269|PubMed:28002401, ECO:0000269|PubMed:30197295}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB21843.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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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 CCDS; CCDS32448.1; -. [Q9C0B1-1]
DR RefSeq; NP_001073901.1; NM_001080432.2. [Q9C0B1-1]
DR PDB; 3LFM; X-ray; 2.50 A; A=32-505.
DR PDB; 4CXW; X-ray; 3.10 A; A=32-505.
DR PDB; 4CXX; X-ray; 2.76 A; A=32-505.
DR PDB; 4CXY; X-ray; 2.65 A; A=32-505.
DR PDB; 4IDZ; X-ray; 2.46 A; A=32-505.
DR PDB; 4IE0; X-ray; 2.53 A; A=32-505.
DR PDB; 4IE4; X-ray; 2.50 A; A=32-505.
DR PDB; 4IE5; X-ray; 1.95 A; A=32-505.
DR PDB; 4IE6; X-ray; 2.50 A; A=32-505.
DR PDB; 4IE7; X-ray; 2.60 A; A=32-505.
DR PDB; 4QHO; X-ray; 2.37 A; A=32-505.
DR PDB; 4QKN; X-ray; 2.20 A; A=32-503.
DR PDB; 4ZS2; X-ray; 2.16 A; A=32-505.
DR PDB; 4ZS3; X-ray; 2.45 A; A=32-505.
DR PDB; 5DAB; X-ray; 2.10 A; A=32-505.
DR PDB; 5F8P; X-ray; 2.20 A; A=32-502.
DR PDB; 5ZMD; X-ray; 3.30 A; A/C/E/G=37-499.
DR PDB; 6AEJ; X-ray; 2.80 A; A=32-159, A=186-505.
DR PDB; 6AK4; X-ray; 2.80 A; A=32-159, A=186-505.
DR PDB; 6AKW; X-ray; 2.20 A; A=32-502.
DR PDB; 7CKK; X-ray; 2.35 A; A=32-500.
DR PDB; 7E8Z; X-ray; 2.55 A; A=32-505.
DR PDBsum; 3LFM; -.
DR PDBsum; 4CXW; -.
DR PDBsum; 4CXX; -.
DR PDBsum; 4CXY; -.
DR PDBsum; 4IDZ; -.
DR PDBsum; 4IE0; -.
DR PDBsum; 4IE4; -.
DR PDBsum; 4IE5; -.
DR PDBsum; 4IE6; -.
DR PDBsum; 4IE7; -.
DR PDBsum; 4QHO; -.
DR PDBsum; 4QKN; -.
DR PDBsum; 4ZS2; -.
DR PDBsum; 4ZS3; -.
DR PDBsum; 5DAB; -.
DR PDBsum; 5F8P; -.
DR PDBsum; 5ZMD; -.
DR PDBsum; 6AEJ; -.
DR PDBsum; 6AK4; -.
DR PDBsum; 6AKW; -.
DR PDBsum; 7CKK; -.
DR PDBsum; 7E8Z; -.
DR AlphaFoldDB; Q9C0B1; -.
DR SMR; Q9C0B1; -.
DR BioGRID; 122520; 81.
DR IntAct; Q9C0B1; 35.
DR MINT; Q9C0B1; -.
DR STRING; 9606.ENSP00000418823; -.
DR BindingDB; Q9C0B1; -.
DR ChEMBL; CHEMBL2331065; -.
DR DrugBank; DB11638; Artenimol.
DR GlyGen; Q9C0B1; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q9C0B1; -.
DR PhosphoSitePlus; Q9C0B1; -.
DR BioMuta; FTO; -.
DR DMDM; 148841515; -.
DR EPD; Q9C0B1; -.
DR jPOST; Q9C0B1; -.
DR MassIVE; Q9C0B1; -.
DR MaxQB; Q9C0B1; -.
DR PaxDb; Q9C0B1; -.
DR PeptideAtlas; Q9C0B1; -.
DR PRIDE; Q9C0B1; -.
DR ProteomicsDB; 79982; -. [Q9C0B1-1]
DR ProteomicsDB; 79983; -. [Q9C0B1-2]
DR ProteomicsDB; 79984; -. [Q9C0B1-3]
DR ProteomicsDB; 79985; -. [Q9C0B1-4]
DR Antibodypedia; 28448; 457 antibodies from 43 providers.
DR DNASU; 79068; -.
DR Ensembl; ENST00000431610.6; ENSP00000415636.2; ENSG00000140718.21. [Q9C0B1-4]
DR Ensembl; ENST00000460382.5; ENSP00000417422.1; ENSG00000140718.21. [Q9C0B1-4]
DR Ensembl; ENST00000463855.1; ENSP00000417843.1; ENSG00000140718.21. [Q9C0B1-2]
DR Ensembl; ENST00000471389.6; ENSP00000418823.1; ENSG00000140718.21. [Q9C0B1-1]
DR GeneID; 79068; -.
DR KEGG; hsa:79068; -.
DR MANE-Select; ENST00000471389.6; ENSP00000418823.1; NM_001080432.3; NP_001073901.1.
DR UCSC; uc002ehr.4; human. [Q9C0B1-1]
DR CTD; 79068; -.
DR DisGeNET; 79068; -.
DR GeneCards; FTO; -.
DR HGNC; HGNC:24678; FTO.
DR HPA; ENSG00000140718; Low tissue specificity.
DR MalaCards; FTO; -.
DR MIM; 601665; phenotype.
DR MIM; 610966; gene.
DR MIM; 612460; phenotype.
DR MIM; 612938; phenotype.
DR neXtProt; NX_Q9C0B1; -.
DR OpenTargets; ENSG00000140718; -.
DR Orphanet; 210144; Lethal polymalformative syndrome, Boissel type.
DR PharmGKB; PA152208656; -.
DR VEuPathDB; HostDB:ENSG00000140718; -.
DR eggNOG; ENOG502QR31; Eukaryota.
DR GeneTree; ENSGT00390000017730; -.
DR HOGENOM; CLU_041676_0_0_1; -.
DR InParanoid; Q9C0B1; -.
DR OMA; GEKACWR; -.
DR OrthoDB; 1300974at2759; -.
DR PhylomeDB; Q9C0B1; -.
DR TreeFam; TF333296; -.
DR BRENDA; 1.14.11.53; 2681.
DR PathwayCommons; Q9C0B1; -.
DR Reactome; R-HSA-73943; Reversal of alkylation damage by DNA dioxygenases.
DR SABIO-RK; Q9C0B1; -.
DR SignaLink; Q9C0B1; -.
DR SIGNOR; Q9C0B1; -.
DR BioGRID-ORCS; 79068; 19 hits in 1078 CRISPR screens.
DR ChiTaRS; FTO; human.
DR GeneWiki; FTO_gene; -.
DR GenomeRNAi; 79068; -.
DR Pharos; Q9C0B1; Tchem.
DR PRO; PR:Q9C0B1; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q9C0B1; protein.
DR Bgee; ENSG00000140718; Expressed in cortical plate and 213 other tissues.
DR ExpressionAtlas; Q9C0B1; baseline and differential.
DR Genevisible; Q9C0B1; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0016607; C:nuclear speck; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
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:1990931; F:mRNA N6-methyladenosine dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0035516; F:oxidative DNA demethylase activity; IDA:UniProtKB.
DR GO; GO:0035515; F:oxidative RNA demethylase activity; IDA:UniProtKB.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:1990984; F:tRNA demethylase activity; IDA:UniProtKB.
DR GO; GO:0060612; P:adipose tissue development; IEA:Ensembl.
DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; IDA:UniProtKB.
DR GO; GO:0080111; P:DNA demethylation; IDA:BHF-UCL.
DR GO; GO:0061157; P:mRNA destabilization; IDA:UniProtKB.
DR GO; GO:0070989; P:oxidative demethylation; IDA:BHF-UCL.
DR GO; GO:0035552; P:oxidative single-stranded DNA demethylation; IDA:UniProtKB.
DR GO; GO:0035553; P:oxidative single-stranded RNA demethylation; IDA:UniProtKB.
DR GO; GO:0090335; P:regulation of brown fat cell differentiation; IMP:UniProtKB.
DR GO; GO:0010883; P:regulation of lipid storage; IMP:UniProtKB.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0044065; P:regulation of respiratory system process; IEA:Ensembl.
DR GO; GO:0070350; P:regulation of white fat cell proliferation; IEA:Ensembl.
DR GO; GO:0042245; P:RNA repair; IDA:BHF-UCL.
DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl.
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 3D-structure; Acetylation; Alternative splicing; Cytoplasm; Dioxygenase;
KW Disease variant; Iron; Metal-binding; Nucleus; Obesity; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..505
FT /note="Alpha-ketoglutarate-dependent dioxygenase FTO"
FT /id="PRO_0000286163"
FT REGION 32..327
FT /note="Fe2OG dioxygenase domain"
FT /evidence="ECO:0000269|PubMed:20376003"
FT REGION 213..224
FT /note="Loop L1; predicted to block binding of double-
FT stranded DNA or RNA"
FT /evidence="ECO:0000269|PubMed:20376003"
FT BINDING 96
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0007744|PDB:3LFM"
FT BINDING 108
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0007744|PDB:3LFM"
FT BINDING 205
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0000269|PubMed:25452335, ECO:0007744|PDB:3LFM,
FT ECO:0007744|PDB:4QKN"
FT BINDING 231..234
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0007744|PDB:3LFM"
FT BINDING 231
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0000269|PubMed:25452335, ECO:0000305|PubMed:23547775,
FT ECO:0000305|PubMed:25452335, ECO:0000305|PubMed:26457839,
FT ECO:0000305|PubMed:28553460, ECO:0007744|PDB:3LFM,
FT ECO:0007744|PDB:4CXW, ECO:0007744|PDB:4CXX,
FT ECO:0007744|PDB:4CXY, ECO:0007744|PDB:4IDZ,
FT ECO:0007744|PDB:4IE0, ECO:0007744|PDB:4IE4,
FT ECO:0007744|PDB:4IE5, ECO:0007744|PDB:4IE6,
FT ECO:0007744|PDB:4IE7, ECO:0007744|PDB:4QKN,
FT ECO:0007744|PDB:4ZS2, ECO:0007744|PDB:4ZS3"
FT BINDING 233
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0000305|PubMed:23547775, ECO:0000305|PubMed:25452335,
FT ECO:0000305|PubMed:26457839, ECO:0000305|PubMed:28553460,
FT ECO:0007744|PDB:3LFM, ECO:0007744|PDB:4CXW,
FT ECO:0007744|PDB:4CXX, ECO:0007744|PDB:4CXY,
FT ECO:0007744|PDB:4IDZ, ECO:0007744|PDB:4IE0,
FT ECO:0007744|PDB:4IE4, ECO:0007744|PDB:4IE5,
FT ECO:0007744|PDB:4IE6, ECO:0007744|PDB:4IE7,
FT ECO:0007744|PDB:4QKN, ECO:0007744|PDB:4ZS2,
FT ECO:0007744|PDB:4ZS3"
FT BINDING 295
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26457839,
FT ECO:0007744|PDB:3LFM, ECO:0007744|PDB:4QKN,
FT ECO:0007744|PDB:4ZS2, ECO:0007744|PDB:4ZS3"
FT BINDING 307
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0000305|PubMed:23547775, ECO:0000305|PubMed:25452335,
FT ECO:0000305|PubMed:26457839, ECO:0000305|PubMed:28553460,
FT ECO:0007744|PDB:3LFM, ECO:0007744|PDB:4CXW,
FT ECO:0007744|PDB:4CXX, ECO:0007744|PDB:4CXY,
FT ECO:0007744|PDB:4IDZ, ECO:0007744|PDB:4IE0,
FT ECO:0007744|PDB:4IE4, ECO:0007744|PDB:4IE5,
FT ECO:0007744|PDB:4IE6, ECO:0007744|PDB:4IE7,
FT ECO:0007744|PDB:4QKN, ECO:0007744|PDB:4ZS2,
FT ECO:0007744|PDB:4ZS3"
FT BINDING 316..318
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26457839,
FT ECO:0007744|PDB:3LFM, ECO:0007744|PDB:4QKN,
FT ECO:0007744|PDB:4ZS2, ECO:0007744|PDB:4ZS3"
FT BINDING 320
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0007744|PDB:3LFM"
FT BINDING 322
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:20376003,
FT ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26457839,
FT ECO:0007744|PDB:3LFM, ECO:0007744|PDB:4QKN,
FT ECO:0007744|PDB:4ZS2"
FT MOD_RES 4
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 216
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VAR_SEQ 1..445
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_025002"
FT VAR_SEQ 1..399
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_025003"
FT VAR_SEQ 1..378
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_025004"
FT VAR_SEQ 379..413
FT /note="LRQFWFQGNRYRKCTDWWCQPMAQLEALWKKMEGV -> MEWRKVSECNSVE
FT PCREVKKWPYRCIHHGKNFSRM (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_025005"
FT VAR_SEQ 446..455
FT /note="QNLRREWHAR -> MACQGREECW (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_025006"
FT VARIANT 271
FT /note="H -> P (found in a patient with microcephaly,
FT developmental delay, behavioral abnormalities, dysmorphic
FT facial features, hypotonia and other various phenotypic
FT abnormalities; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:26740239"
FT /id="VAR_076423"
FT VARIANT 316
FT /note="R -> Q (in GDFD; has no residual normal activity,
FT impaired ability to demethylate N(6)-methyladenosine RNAs
FT (m6A) RNAs; dbSNP:rs121918214)"
FT /evidence="ECO:0000269|PubMed:19559399,
FT ECO:0000269|PubMed:22002720"
FT /id="VAR_063252"
FT VARIANT 319
FT /note="S -> F (in GDFD; reduced enzyme activity;
FT dbSNP:rs781028867)"
FT /evidence="ECO:0000269|PubMed:26378117"
FT /id="VAR_075468"
FT VARIANT 322
FT /note="R -> Q (in GDFD; dbSNP:rs745616565)"
FT /evidence="ECO:0000269|PubMed:26697951"
FT /id="VAR_075469"
FT VARIANT 405
FT /note="A -> V (in dbSNP:rs16952624)"
FT /id="VAR_032078"
FT MUTAGEN 96
FT /note="R->M,W: Almost abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:20376003"
FT MUTAGEN 108
FT /note="Y->A: Abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:20376003"
FT MUTAGEN 114
FT /note="F->D: Perturbs interaction between N-terminal and C-
FT terminal domains and strongly reduces enzyme activity."
FT /evidence="ECO:0000269|PubMed:20376003"
FT MUTAGEN 231..233
FT /note="HHD->AHA: Abolishes ability to demethylate N(6)-
FT methyladenosine RNAs (m6A) RNAs."
FT /evidence="ECO:0000269|PubMed:22002720"
FT MUTAGEN 234
FT /note="E->P: Abolishes enzyme activity. Abolishes ability
FT to demethylate N(6)-methyladenosine RNAs (m6A) RNAs; when
FT associated with Q-322."
FT /evidence="ECO:0000269|PubMed:20376003"
FT MUTAGEN 392
FT /note="C->D: Perturbs interaction between N-terminal and C-
FT terminal domains and strongly reduces enzyme activity."
FT /evidence="ECO:0000269|PubMed:20376003"
FT CONFLICT 316
FT /note="R -> W (in Ref. 1; BAB21843 and 3; AAH03583/
FT AAH30798/AAI32893)"
FT /evidence="ECO:0000305"
FT STRAND 35..37
FT /evidence="ECO:0007829|PDB:4QKN"
FT HELIX 38..45
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 49..52
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 54..56
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 59..74
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 79..85
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 88..101
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 104..108
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 111..114
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 127..129
FT /evidence="ECO:0007829|PDB:5ZMD"
FT HELIX 130..162
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 190..196
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 201..207
FT /evidence="ECO:0007829|PDB:4IE5"
FT TURN 209..211
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 212..214
FT /evidence="ECO:0007829|PDB:3LFM"
FT STRAND 219..221
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 225..231
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 242..248
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 271..276
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 280..282
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 284..288
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 293..297
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 301..304
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 305..310
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 316..322
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 327..330
FT /evidence="ECO:0007829|PDB:5F8P"
FT HELIX 331..342
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 361..377
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 379..384
FT /evidence="ECO:0007829|PDB:4IE5"
FT TURN 385..387
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 389..391
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 397..422
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 423..426
FT /evidence="ECO:0007829|PDB:4IDZ"
FT HELIX 428..457
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 459..463
FT /evidence="ECO:0007829|PDB:4IE5"
FT HELIX 466..468
FT /evidence="ECO:0007829|PDB:4IE5"
FT STRAND 482..485
FT /evidence="ECO:0007829|PDB:5DAB"
FT HELIX 490..500
FT /evidence="ECO:0007829|PDB:4IE5"
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
