FTO_CANLF
ID FTO_CANLF Reviewed; 506 AA.
AC F1PLN3;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 10-APR-2019, sequence version 3.
DT 03-AUG-2022, entry version 57.
DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO {ECO:0000250|UniProtKB:Q9C0B1};
DE AltName: Full=Fat mass and obesity-associated protein {ECO:0000250|UniProtKB:Q9C0B1};
DE AltName: Full=U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO {ECO:0000250|UniProtKB:Q9C0B1};
DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9C0B1};
DE AltName: Full=U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO {ECO:0000250|UniProtKB:Q9C0B1};
DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9C0B1};
DE AltName: Full=mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO {ECO:0000250|UniProtKB:Q9C0B1};
DE Short=m6A(m)-demethylase FTO {ECO:0000250|UniProtKB:Q9C0B1};
DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9C0B1};
DE AltName: Full=mRNA N(6)-methyladenosine demethylase FTO {ECO:0000250|UniProtKB:Q9C0B1};
DE EC=1.14.11.53 {ECO:0000250|UniProtKB:Q9C0B1};
DE AltName: Full=tRNA N1-methyl adenine demethylase FTO;
DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9C0B1};
GN Name=FTO;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615 {ECO:0000312|Proteomes:UP000002254};
RN [1] {ECO:0000312|Proteomes:UP000002254}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Boxer {ECO:0000312|Proteomes:UP000002254};
RX PubMed=16341006; DOI=10.1038/nature04338;
RA Lindblad-Toh K., Wade C.M., Mikkelsen T.S., Karlsson E.K., Jaffe D.B.,
RA Kamal M., Clamp M., Chang J.L., Kulbokas E.J. III, Zody M.C., Mauceli E.,
RA Xie X., Breen M., Wayne R.K., Ostrander E.A., Ponting C.P., Galibert F.,
RA Smith D.R., deJong P.J., Kirkness E.F., Alvarez P., Biagi T., Brockman W.,
RA Butler J., Chin C.-W., Cook A., Cuff J., Daly M.J., DeCaprio D., Gnerre S.,
RA Grabherr M., Kellis M., Kleber M., Bardeleben C., Goodstadt L., Heger A.,
RA Hitte C., Kim L., Koepfli K.-P., Parker H.G., Pollinger J.P.,
RA Searle S.M.J., Sutter N.B., Thomas R., Webber C., Baldwin J., Abebe A.,
RA Abouelleil A., Aftuck L., Ait-Zahra M., Aldredge T., Allen N., An P.,
RA Anderson S., Antoine C., Arachchi H., Aslam A., Ayotte L., Bachantsang P.,
RA Barry A., Bayul T., Benamara M., Berlin A., Bessette D., Blitshteyn B.,
RA Bloom T., Blye J., Boguslavskiy L., Bonnet C., Boukhgalter B., Brown A.,
RA Cahill P., Calixte N., Camarata J., Cheshatsang Y., Chu J., Citroen M.,
RA Collymore A., Cooke P., Dawoe T., Daza R., Decktor K., DeGray S.,
RA Dhargay N., Dooley K., Dooley K., Dorje P., Dorjee K., Dorris L.,
RA Duffey N., Dupes A., Egbiremolen O., Elong R., Falk J., Farina A., Faro S.,
RA Ferguson D., Ferreira P., Fisher S., FitzGerald M., Foley K., Foley C.,
RA Franke A., Friedrich D., Gage D., Garber M., Gearin G., Giannoukos G.,
RA Goode T., Goyette A., Graham J., Grandbois E., Gyaltsen K., Hafez N.,
RA Hagopian D., Hagos B., Hall J., Healy C., Hegarty R., Honan T., Horn A.,
RA Houde N., Hughes L., Hunnicutt L., Husby M., Jester B., Jones C., Kamat A.,
RA Kanga B., Kells C., Khazanovich D., Kieu A.C., Kisner P., Kumar M.,
RA Lance K., Landers T., Lara M., Lee W., Leger J.-P., Lennon N., Leuper L.,
RA LeVine S., Liu J., Liu X., Lokyitsang Y., Lokyitsang T., Lui A.,
RA Macdonald J., Major J., Marabella R., Maru K., Matthews C., McDonough S.,
RA Mehta T., Meldrim J., Melnikov A., Meneus L., Mihalev A., Mihova T.,
RA Miller K., Mittelman R., Mlenga V., Mulrain L., Munson G., Navidi A.,
RA Naylor J., Nguyen T., Nguyen N., Nguyen C., Nguyen T., Nicol R., Norbu N.,
RA Norbu C., Novod N., Nyima T., Olandt P., O'Neill B., O'Neill K., Osman S.,
RA Oyono L., Patti C., Perrin D., Phunkhang P., Pierre F., Priest M.,
RA Rachupka A., Raghuraman S., Rameau R., Ray V., Raymond C., Rege F.,
RA Rise C., Rogers J., Rogov P., Sahalie J., Settipalli S., Sharpe T.,
RA Shea T., Sheehan M., Sherpa N., Shi J., Shih D., Sloan J., Smith C.,
RA Sparrow T., Stalker J., Stange-Thomann N., Stavropoulos S., Stone C.,
RA Stone S., Sykes S., Tchuinga P., Tenzing P., Tesfaye S., Thoulutsang D.,
RA Thoulutsang Y., Topham K., Topping I., Tsamla T., Vassiliev H.,
RA Venkataraman V., Vo A., Wangchuk T., Wangdi T., Weiand M., Wilkinson J.,
RA Wilson A., Yadav S., Yang S., Yang X., Young G., Yu Q., Zainoun J.,
RA Zembek L., Zimmer A., Lander E.S.;
RT "Genome sequence, comparative analysis and haplotype structure of the
RT domestic dog.";
RL Nature 438:803-819(2005).
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 Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most
CC prevalent internal modification of messenger RNA (mRNA) in higher
CC eukaryotes. M6A demethylation by FTO affects mRNA expression and
CC stability. Also able to demethylate m6A in U6 small nuclear RNA
CC (snRNA). Mediates demethylation of N(6),2'-O-dimethyladenosine cap
CC (m6A(m)), by demethylating the N(6)-methyladenosine at the second
CC transcribed position of mRNAs and U6 snRNA. Demethylation of m6A(m) in
CC the 5'-cap by FTO affects mRNA stability by promoting susceptibility to
CC decapping. Also acts as a tRNA demethylase by removing N(1)-
CC methyladenine from various tRNAs. Has no activity towards 1-
CC methylguanine. Has no detectable activity towards double-stranded DNA.
CC Also 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. Ability to repair alkylated DNA and RNA is however
CC unsure in vivo. 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. Involved in the regulation of thermogenesis
CC and the control of adipocyte differentiation into brown or white fat
CC cells. Regulates activity of the dopaminergic midbrain circuitry via
CC its ability to demethylate m6A in mRNAs. Plays an oncogenic role in a
CC number of acute myeloid leukemias by enhancing leukemic oncogene-
CC mediated cell transformation: acts by mediating m6A demethylation of
CC target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to
CC promote their expression. {ECO:0000250|UniProtKB:Q8BGW1,
CC 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 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:0000250|UniProtKB:Q9C0B1};
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:0000250|UniProtKB:Q9C0B1};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000250|UniProtKB:Q9C0B1};
CC -!- SUBUNIT: Monomer. May also exist as homodimer.
CC {ECO:0000250|UniProtKB:Q8BGW1}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9C0B1}. 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 -!- 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 -!- SIMILARITY: Belongs to the fto family. {ECO:0000305}.
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DR EMBL; AAEX03001602; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAEX03001603; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR AlphaFoldDB; F1PLN3; -.
DR SMR; F1PLN3; -.
DR STRING; 9615.ENSCAFP00000058279; -.
DR PaxDb; F1PLN3; -.
DR eggNOG; ENOG502QR31; Eukaryota.
DR HOGENOM; CLU_041676_0_0_1; -.
DR InParanoid; F1PLN3; -.
DR TreeFam; TF333296; -.
DR Proteomes; UP000002254; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:1990931; F:mRNA N6-methyladenosine dioxygenase activity; IEA:UniProtKB-EC.
DR GO; GO:0035516; F:oxidative DNA demethylase activity; IEA:InterPro.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; IEA:InterPro.
DR GO; GO:0035552; P:oxidative single-stranded DNA demethylation; IEA:InterPro.
DR GO; GO:0035553; P:oxidative single-stranded RNA demethylation; IEA:InterPro.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:InterPro.
DR GO; GO:0042245; P:RNA repair; IEA:InterPro.
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 3: Inferred from homology;
KW Acetylation; Cytoplasm; Dioxygenase; Iron; Metal-binding; Nucleus;
KW Oxidoreductase; Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..506
FT /note="Alpha-ketoglutarate-dependent dioxygenase FTO"
FT /id="PRO_0000446639"
FT REGION 32..326
FT /note="Fe2OG dioxygenase domain"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT REGION 212..223
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 204
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 230..233
FT /ligand="substrate"
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 232
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 294
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 306
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 315..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 BINDING 321
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT MOD_RES 4
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT MOD_RES 215
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
SQ SEQUENCE 506 AA; 58501 MW; 36964ADF1C3B26A3 CRC64;
MKRTPTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLI LREAGSVPED
LHKEVQEAFL TLHKHGCFFR DLVRIQGKDL LTPVSRILIG NPGCTYKYLN TRLFTVPWPV
KGASTKYDEA GIAAACQTFL KLNDYLQIET IQALEELACK EKSNIDAVPV CIGPDFPRVG
MGSFDGQDEL DIKNRAAYNV TLLNFMDPQK MPYLKEEPYF GMGKMAVSWH HDENLVERSA
VAVYSYSCEG PEEESEDDPQ LEGRDPDTWH VGFKISWDIE TPGLAIPLHQ GDCYFMLDDL
NATHQHCVLA GLPPRFSSTH RVAECSTGTL DYILQRCQLA LQNVRDEADN GDVSLKSFEP
VVLKQGEEIH NEVEFEWLRQ YWFQGNRYRK CTDWWCQPMT QLEGLWKKME GVTNAVLHEV
RREGVPVEQR NEILTAILAL LTTRQNLRRE WHARCQSRIA RTLPVDQKPE CRPYWEKDDP
SMPLPFDLTD IVSELRGEFG TLPWSA
