FTO_RAT
ID FTO_RAT Reviewed; 502 AA.
AC Q2A121;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 04-APR-2006, sequence version 1.
DT 03-AUG-2022, entry version 90.
DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO {ECO:0000305};
DE AltName: Full=Fat mass and obesity-associated protein {ECO:0000303|PubMed:18218688};
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:0000250|UniProtKB:Q9C0B1};
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:18218688, ECO:0000312|RGD:1305121};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=Wistar;
RX PubMed=17143547;
RA Trueb B., Taeschler S., Schild C., Lang N.P.;
RT "Expression of phosphoproteins and amelotin in teeth.";
RL Int. J. Mol. Med. 19:49-54(2007).
RN [2]
RP INDUCTION BY FASTING, AND TISSUE SPECIFICITY.
RX PubMed=18218688; DOI=10.1210/en.2007-1457;
RA Fredriksson R., Hagglund M., Olszewski P.K., Stephansson O.,
RA Jacobsson J.A., Olszewska A.M., Levine A.S., Lindblom J., Schioth H.B.;
RT "The obesity gene, FTO, is of ancient origin, up-regulated during food
RT deprivation and expressed in neurons of feeding-related nuclei of the
RT brain.";
RL Endocrinology 149:2062-2071(2008).
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 (By similarity). Regulates activity of the dopaminergic midbrain
CC circuitry via its ability to demethylate m6A in mRNAs (By similarity).
CC {ECO:0000250|UniProtKB:Q8BGW1, 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 -!- ACTIVITY REGULATION: Activated by ascorbate. Inhibited by N-
CC oxalylglycine, fumarate and succinate. {ECO:0000250|UniProtKB:Q8BGW1}.
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 -!- TISSUE SPECIFICITY: Ubiquitous (PubMed:17143547, PubMed:18218688).
CC Highly expressed in teeth and weakly in bone (PubMed:17143547).
CC {ECO:0000269|PubMed:17143547, ECO:0000269|PubMed:18218688}.
CC -!- INDUCTION: Up-regulated in the hypothalamus after 48 hours fasting.
CC {ECO:0000269|PubMed:18218688}.
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; AM233906; CAJ80872.1; -; mRNA.
DR RefSeq; NP_001034802.1; NM_001039713.1.
DR AlphaFoldDB; Q2A121; -.
DR SMR; Q2A121; -.
DR STRING; 10116.ENSRNOP00000015718; -.
DR PhosphoSitePlus; Q2A121; -.
DR jPOST; Q2A121; -.
DR PaxDb; Q2A121; -.
DR PRIDE; Q2A121; -.
DR Ensembl; ENSRNOT00000015718; ENSRNOP00000015718; ENSRNOG00000011728.
DR GeneID; 291905; -.
DR KEGG; rno:291905; -.
DR CTD; 79068; -.
DR RGD; 1305121; Fto.
DR eggNOG; ENOG502QR31; Eukaryota.
DR GeneTree; ENSGT00390000017730; -.
DR HOGENOM; CLU_041676_0_0_1; -.
DR InParanoid; Q2A121; -.
DR OrthoDB; 1300974at2759; -.
DR PhylomeDB; Q2A121; -.
DR TreeFam; TF333296; -.
DR Reactome; R-RNO-73943; Reversal of alkylation damage by DNA dioxygenases.
DR PRO; PR:Q2A121; -.
DR Proteomes; UP000002494; Chromosome 19.
DR Bgee; ENSRNOG00000011728; Expressed in cerebellum and 19 other tissues.
DR ExpressionAtlas; Q2A121; baseline and differential.
DR Genevisible; Q2A121; RN.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0016607; C:nuclear speck; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0043734; F:DNA-N1-methyladenine dioxygenase activity; ISS: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; ISS:UniProtKB.
DR GO; GO:0035515; F:oxidative RNA demethylase activity; ISS:UniProtKB.
DR GO; GO:1990984; F:tRNA demethylase activity; ISS:UniProtKB.
DR GO; GO:0060612; P:adipose tissue development; ISO:RGD.
DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; ISS:UniProtKB.
DR GO; GO:0080111; P:DNA demethylation; ISO:RGD.
DR GO; GO:0061157; P:mRNA destabilization; ISS:UniProtKB.
DR GO; GO:0070989; P:oxidative demethylation; ISO:RGD.
DR GO; GO:0035552; P:oxidative single-stranded DNA demethylation; ISS:UniProtKB.
DR GO; GO:0035553; P:oxidative single-stranded RNA demethylation; ISS:UniProtKB.
DR GO; GO:0090335; P:regulation of brown fat cell differentiation; ISO:RGD.
DR GO; GO:0010883; P:regulation of lipid storage; ISO:RGD.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISO:RGD.
DR GO; GO:0044065; P:regulation of respiratory system process; ISO:RGD.
DR GO; GO:0070350; P:regulation of white fat cell proliferation; ISO:RGD.
DR GO; GO:0042245; P:RNA repair; ISO:RGD.
DR GO; GO:0001659; P:temperature homeostasis; ISO:RGD.
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 2: Evidence at transcript level;
KW Acetylation; Cytoplasm; Dioxygenase; Iron; Metal-binding; Nucleus;
KW Oxidoreductase; Reference proteome.
FT CHAIN 1..502
FT /note="Alpha-ketoglutarate-dependent dioxygenase FTO"
FT /id="PRO_0000286166"
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"
SQ SEQUENCE 502 AA; 57972 MW; DEF554159E312EA7 CRC64;
MKRVQTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLV FREAGSIPEE
LHKEVPEAFL TLHKHGCLFR DLVRIQGKDV LTPVSRILIG DPGCTYKYLN TRLFTVPWPV
KGCTINYTEA EIAAACQTFL KLNDYLQVET IQALEELAIK EKANEDAVPL CMAEFPRAGV
GPSCDDEVDL KSRAAYNVTL LNFMDPQKMP YLKEEPYFGM GKMAVSWHHD ENLVDRSAVA
VYSYSCEGSE DESDDESSFE GRDPDTWHVG FKISWDIETP GLTIPLHQGD CYFMLDDLNA
THQHCVLAGS QPRFSSTHRV AECSTGTLDY ILQRCQLALQ NVLNDSDNGD VSLKSFEPAV
LKQGEEIHNE VEFEWLRQFW FQGNRYKICT DWWCEPMTQL EGLWKKMESV TNAVLREVKR
EGLSVEQRSE ILSAVLIPLT MRQNLRKEWH ARCQARVVRT LPAQQKPDCR PYWEKDDPSM
PLPFDLTDVV SEIRSQLLEA RS
