Protein: Alpha-ketoglutarate-dependent dioxygenase FTO (Fat mass and obesity-associated protein) (Protein fatso) (U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO) (EC 1.14.11.-) (U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO) (EC 1.14.11.-) (mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO) (m6A(m)-demethylase FTO) (EC 1.14.11.-) (mRNA N(6)-methyladenosine demethylase FTO) (EC 1.14.11.53) (tRNA N1-methyl adenine demethylase FTO) (EC 1.14.11.-) (Q8BGW1)
Organism: Mus musculus (Mouse)
Function: RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis. Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. M6A demethylation by FTO affects mRNA expression and stability (By similarity). Also able to demethylate m6A in U6 small nuclear RNA (snRNA) (By similarity). Mediates demethylation of N(6),2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N(6)-methyladenosine at the second transcribed position of mRNAs and U6 snRNA. Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping (By similarity). Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs (By similarity). Has no activity towards 1-methylguanine (By similarity). Has no detectable activity towards double-stranded DNA (By similarity). Also able to repair alkylated DNA and RNA by oxidative demethylation: demethylates single-stranded RNA containing 3-methyluracil, single-stranded DNA containing 3-methylthymine and has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine. Ability to repair alkylated DNA and RNA is however unsure in vivo. Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation. Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells. Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs.
Subcellular location: Nucleus {ECO:0000269|PubMed:17991826, ECO:0000269|PubMed:19234441, ECO:0000269|PubMed:19680540}. Nucleus speckle {ECO:0000250|UniProtKB:Q9C0B1}. Cytoplasm {ECO:0000250|UniProtKB:Q9C0B1}. Note=Localizes mainly in the nucleus, where it is able to demethylate N(6)-methyladenosine (m6A) and N(6),2'-O-dimethyladenosine cap (m6A(m)) in U6 small nuclear RNA (snRNA), N(1)-methyladenine from tRNAs and internal m6A in mRNAs. In the cytoplasm, mediates demethylation of m6A and m6A(m) in mRNAs and N(1)-methyladenine from tRNAs. {ECO:0000250|UniProtKB:Q9C0B1}.
InterPro domains:
- IPR037151: Alpha-ketoglutarate-dependent dioxygenase AlkB-like superfamily (homologous_superfamily) [30-327]
- IPR038413: FTO, C-terminal domain superfamily (homologous_superfamily) [328-461]
- IPR024367: Alpha-ketoglutarate-dependent dioxygenase FTO, catalytic domain (domain) [35-323]
- IPR024366: Alpha-ketoglutarate-dependent dioxygenase FTO, C-terminal (domain) [326-494]
- IPR032868: Alpha-ketoglutarate-dependent dioxygenase FTO (family) [1-499]
Sequence:
MKRVQTAEEREREAKKLRLLEELEDTWLPYLTPKDDEFYQQWQLKYPKLVFREAGSIPEELHKEVPEAFLTLHKHGCLFRDVVRIQGKDVLTPVSRILIGDPGCTYKYLNTRLFTVPWPVKGCTVKYTEAEIAAACQTFLKLNDYLQVETIQALEELAVREKANEDAVPLCMAEFPRAGVGPSCDDEVDLKSRAAYNVTLLNFMDPQKMPYLKEEPYFGMGKMAVSWHHDENLVDRSAVAVYSYSCEGSEDESEDESSFEGRDPDTWHVGFKISWDIETPGLTIPLHQGDCYFMLDDLNATHQHCVLAGSQPRFSSTHRVAECSTGTLDYILERCQLALQNVLNDSDDGDVSLKSFDPAVLKQGEEIHNEVEFEWLRQFWFQGNRYKLCTDWWCEPMTHLEGLWKKMESMTNAVLREVKREGLPVEQRSEILSAILVPLTVRQNLRKEWHARCQSRVVRTLPVQQKPDCRPYWEKDDPSMPLPFDLTDVVSELRGQLLEARS
Predicted GO terms:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0032451 (demethylase activity), GO:0016491 (oxidoreductase activity), GO:0140640 (catalytic activity, acting on a nucleic acid), GO:0043167 (ion binding), GO:0005515 (protein binding), GO:0140098 (catalytic activity, acting on RNA), GO:0051213 (dioxygenase activity), GO:0016705 (oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen), GO:0043169 (cation binding), GO:0140097 (catalytic activity, acting on DNA), GO:0140101 (catalytic activity, acting on a tRNA), GO:0016706 (2-oxoglutarate-dependent dioxygenase activity), GO:0046872 (metal ion binding), GO:0046914 (transition metal ion binding), GO:0005506 (iron ion binding), GO:0008198 (ferrous iron binding)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0009987 (cellular process), GO:0048519 (negative regulation of biological process), GO:0019222 (regulation of metabolic process), GO:0032879 (regulation of localization), GO:0006807 (nitrogen compound metabolic process), GO:0071704 (organic substance metabolic process), GO:0070988 (demethylation), GO:0009892 (negative regulation of metabolic process), GO:0065008 (regulation of biological quality), GO:0050793 (regulation of developmental process), GO:0044237 (cellular metabolic process), GO:0050794 (regulation of cellular process), GO:0009893 (positive regulation of metabolic process), GO:0051716 (cellular response to stimulus), GO:0044238 (primary metabolic process), GO:0006950 (response to stress), GO:0048523 (negative regulation of cellular process), GO:0048522 (positive regulation of cellular process), GO:0051172 (negative regulation of nitrogen compound metabolic process), GO:0043487 (regulation of RNA stability), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0046483 (heterocycle metabolic process), GO:0080111 (DNA demethylation), GO:0060255 (regulation of macromolecule metabolic process), GO:0010883 (regulation of lipid storage), GO:0006725 (cellular aromatic compound metabolic process), GO:0034641 (cellular nitrogen compound metabolic process), GO:0031324 (negative regulation of cellular metabolic process), GO:0043170 (macromolecule metabolic process), GO:0009894 (regulation of catabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:0006139 (nucleobase-containing compound metabolic process), GO:0031325 (positive regulation of cellular metabolic process), GO:0033554 (cellular response to stress), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0009889 (regulation of biosynthetic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0045595 (regulation of cell differentiation), GO:0031323 (regulation of cellular metabolic process), GO:0009890 (negative regulation of biosynthetic process), GO:0080090 (regulation of primary metabolic process), GO:0044260 (cellular macromolecule metabolic process), GO:0009896 (positive regulation of catabolic process), GO:0045598 (regulation of fat cell differentiation), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0051246 (regulation of protein metabolic process), GO:0006974 (cellular response to DNA damage stimulus), GO:0043488 (regulation of mRNA stability), GO:0051248 (negative regulation of protein metabolic process), GO:0050779 (RNA destabilization), GO:0010468 (regulation of gene expression), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0051254 (positive regulation of RNA metabolic process), GO:0043412 (macromolecule modification), GO:0034248 (regulation of amide metabolic process), GO:0090304 (nucleic acid metabolic process), GO:0031326 (regulation of cellular biosynthetic process), GO:0006259 (DNA metabolic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0031331 (positive regulation of cellular catabolic process), GO:0010558 (negative regulation of macromolecule biosynthetic process), GO:0031327 (negative regulation of cellular biosynthetic process), GO:0051252 (regulation of RNA metabolic process), GO:0031329 (regulation of cellular catabolic process), GO:0010629 (negative regulation of gene expression), GO:0034249 (negative regulation of amide metabolic process), GO:0017148 (negative regulation of translation), GO:0016070 (RNA metabolic process), GO:0006304 (DNA modification), GO:0061013 (regulation of mRNA catabolic process), GO:0061014 (positive regulation of mRNA catabolic process), GO:0006281 (DNA repair), GO:0009451 (RNA modification), GO:2000112 (regulation of cellular macromolecule biosynthetic process), GO:0090335 (regulation of brown fat cell differentiation), GO:0006417 (regulation of translation), GO:0061157 (mRNA destabilization), GO:1903311 (regulation of mRNA metabolic process), GO:2000113 (negative regulation of cellular macromolecule biosynthetic process), GO:1903313 (positive regulation of mRNA metabolic process), GO:0010608 (post-transcriptional regulation of gene expression), GO:0035510 (DNA dealkylation), GO:0006307 (DNA dealkylation involved in DNA repair)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0016604 (nuclear body), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0016020 (membrane), GO:0005829 (cytosol), GO:0005737 (cytoplasm), GO:0071944 (cell periphery), GO:0031974 (membrane-enclosed lumen), GO:0005654 (nucleoplasm), GO:0043233 (organelle lumen), GO:0043229 (intracellular organelle), GO:0016607 (nuclear speck), GO:0043227 (membrane-bounded organelle), GO:0005886 (plasma membrane), GO:0043231 (intracellular membrane-bounded organelle), GO:0070013 (intracellular organelle lumen), GO:0031981 (nuclear lumen), GO:0005634 (nucleus)