FTO_PONAB
ID FTO_PONAB Reviewed; 505 AA.
AC Q5R7X0;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 64.
DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO {ECO:0000305};
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: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:0000250|UniProtKB:Q9C0B1};
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
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 -!- 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}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; CR859989; CAH92140.1; -; mRNA.
DR RefSeq; NP_001126250.1; NM_001132778.1.
DR AlphaFoldDB; Q5R7X0; -.
DR SMR; Q5R7X0; -.
DR STRING; 9601.ENSPPYP00000008304; -.
DR PRIDE; Q5R7X0; -.
DR GeneID; 100173222; -.
DR KEGG; pon:100173222; -.
DR CTD; 79068; -.
DR eggNOG; ENOG502QR31; Eukaryota.
DR InParanoid; Q5R7X0; -.
DR OrthoDB; 1300974at2759; -.
DR Proteomes; UP000001595; Unplaced.
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:0006307; P:DNA dealkylation involved in DNA repair; ISS:UniProtKB.
DR GO; GO:0061157; P:mRNA destabilization; ISS:UniProtKB.
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: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 2: Evidence at transcript level;
KW Acetylation; Cytoplasm; Dioxygenase; Iron; Metal-binding; Nucleus;
KW Oxidoreductase; Phosphoprotein; Reference proteome.
FT CHAIN 1..505
FT /note="Alpha-ketoglutarate-dependent dioxygenase FTO"
FT /id="PRO_0000286165"
FT REGION 32..327
FT /note="Fe2OG dioxygenase domain"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT REGION 213..224
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 205
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 231..234
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 231
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 233
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 295
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 307
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 316..318
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 320
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
FT BINDING 322
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 216
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0B1"
SQ SEQUENCE 505 AA; 58423 MW; B6551B0D2A20D591 CRC64;
MKRTPTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLI LREASSVSEE
LHKEVQEAFL TMHKHGCLFR DLVRIQGKDL LTPVSRILIG NPGCTYKYLN TRLFTVPWPV
KGSNIKHTEA EIAAACETFL KLNDYLQIET IQALEELAAK EKANEDTVPL CMSADFPRVG
MGSSYNGQDE VDIKSRAAYN VTLLNFMDPQ KMPYLKEEPY FGMGKMAVSW HHDENLVDRS
AVAVYSYSCE GPEEESEDDS HLEGRDPDIW HVGFKISWDI ETPGLAIPLH QGDCYFMLDD
LNATHQHCVL AGSQPRFSST HRVAECSTGT LDYILQRCQL APQNVRDDVE NDDVSLKSFE
PAVLKQGEEI HNEVEFEWLR QFWFQGNRYR KCTDWWCQPM AQLEALWKKM EAVTNAVLHE
VKREGLPVEQ RNEILTAILA SLTARQNLRR EWHARCQSRI ARTLPADQKP ECRPYWEKDD
VSMPLPFDLT DIVSELRGQL LEAKP
