Modomics - A Database of RNA Modifications

ID Card:

Full name:	Alpha-ketoglutarate-dependent dioxygenase FTO
Synonym:	KIAA1752
GI:	122937263
UniProt:	Q9C0B1
Structures:	\| 3LFM \| 4CXW \| 4CXX \| 4CXY \| 4IDZ \| 4IE0 \| 4IE4 \| 4IE5 \| 4IE6 \| 4IE7 \| 4QHO \| 4QKN \| 4ZS2 \| 4ZS3 \| 5DAB \| 5F8P \| 5ZMD \| 6AEJ \| 6AK4 \| 6AKW \| 7CKK \| 7E8Z \| 7WCV \|
Alpha Fold Predicted Structure:	AF-Q9C0B1-F1
Enzyme type:	demethylase
Position of modification - modification:	m:many - A m:many - f6A m:many - hm6A

PDB Structures:

3LFM

Structure Description:

Title:
Classification:
Technique:

Abstract of the PDB Structure's related Publication:

Recent studies have unequivocally associated the fat mass and obesity-associated (FTO) gene with the risk of obesity. In vitro FTO protein is an AlkB-like DNA/RNA demethylase with a strong preference for 3-methylthymidine (3-meT) in single-stranded DNA or 3-methyluracil (3-meU) in single-stranded RNA. Here we report the crystal structure of FTO in complex with the mononucleotide 3-meT. FTO comprises an amino-terminal AlkB-like domain and a carboxy-terminal domain with a novel fold. Biochemical assays show that these two domains interact with each other, which is required for FTO catalytic activity. In contrast with the structures of other AlkB members, FTO possesses an extra loop covering one side of the conserved jelly-roll motif. Structural comparison shows that this loop selectively competes with the unmethylated strand of the DNA duplex for binding to FTO, suggesting that it has an important role in FTO selection against double-stranded nucleic acids. The ability of FTO to distinguish 3-meT or 3-meU from other nucleotides is conferred by its hydrogen-bonding interaction with the two carbonyl oxygen atoms in 3-meT or 3-meU. Taken together, these results provide a structural basis for understanding FTO substrate-specificity, and serve as a foundation for the rational design of FTO inhibitors.

Download RCSB-PDB Structures:

Pdb Files	3LFM.pdb 4CXW.pdb 4CXX.pdb 4CXY.pdb 4IDZ.pdb 4IE0.pdb 4IE4.pdb 4IE5.pdb 4IE6.pdb 4IE7.pdb 4QHO.pdb 4QKN.pdb 4ZS2.pdb 4ZS3.pdb 5DAB.pdb 5F8P.pdb 5ZMD.pdb 6AEJ.pdb 6AK4.pdb 6AKW.pdb 7CKK.pdb 7E8Z.pdb 7WCV.pdb
Pdbx/mmCIF Files	3LFM.cif 4CXW.cif 4CXX.cif 4CXY.cif 4IDZ.cif 4IE0.cif 4IE4.cif 4IE5.cif 4IE6.cif 4IE7.cif 4QHO.cif 4QKN.cif 4ZS2.cif 4ZS3.cif 5DAB.cif 5F8P.cif 5ZMD.cif 6AEJ.cif 6AK4.cif 6AKW.cif 7CKK.cif 7E8Z.cif 7WCV.cif

Protein sequence:

MKRTPTAEEREREAKKLRLLEELEDTWLPYLTPKDDEFYQQWQLKYPKLILREASSVSEELHKEVQEAFLTLHKHGCLFRDLVRIQGKDLLTPVSRILIGNPGCTYKYLNTRLFTVPWPVKGSNIKHTEAEIAAACETFLKLNDYLQIETIQALEELAAKEKANEDAVPLCMSADFPRVGMGSSYNGQDEVDIKSRAAYNVTLLNFMDPQKMPYLKEEPYFGMGKMAVSWHHDENLVDRSAVAVYSYSCEGPEEESEDDSHLEGRDPDIWHVGFKISWDIETPGLAIPLHQGDCYFMLDDLNATHQHCVLAGSQPRFSSTHRVAECSTGTLDYILQRCQLALQNVCDDVDNDDVSLKSFEPAVLKQGEEIHNEVEFEWLRQFWFQGNRYRKCTDWWCQPMAQLEALWKKMEGVTNAVLHEVKREGLPVEQRNEILTAILASLTARQNLRREWHARCQSRIARTLPADQKPECRPYWEKDDASMPLPFDLTDIVSELRGQLLEAKP

Comments:

The human fat mass and obesity-associated protein FTO catalyses the removal of m6A in vitro and in vivo. It is a member of the non-haem FeII/a-ketoglutarate (a-KG)-dependent AlkB family demethylases that mainly catalyse oxidative demethylation of N-alkylated nucleic acid bases. FTO oxidizes m6A to hm6A and f6A in RNA in a step-wise manner. FTO was identified in several genome-wide-association studies to be associated with obesity and type II diabetes.

Reaction	Substrate	Position	Transcript Region	Cellular Localization	References
m6A:A	mRNA (m)	many	Pu[G>A]m6AC[A/C/U]	Nucleoplasm	22002720
m6A:hm6A	mRNA (m)	many	Pu[G>A]m6AC[A/C/U]	Nucleoplasm	23653210
hm6A:f6A	mRNA (m)	many	Pu[G>A]m6AC[A/C/U]	Nucleoplasm	23653210

Alpha Fold Predicted Structure:

Clear Selection and Reset Camera

Protein sequence:

M K R T P T A E E R E R E A K K L R L L E E L E D T W L P Y L T P K D D E F Y Q Q W Q L K Y P K L I L R E A S S V S E E L H K E V Q E A F L T L H K H G C L F R D L V R I Q G K D L L T P V S R I L I G N P G C T Y K Y L N T R L F T V P W P V K G S N I K H T E A E I A A A C E T F L K L N D Y L Q I E T I Q A L E E L A A K E K A N E D A V P L C M S A D F P R V G M G S S Y N G Q D E V D I K S R A A Y N V T L L N F M D P Q K M P Y L K E E P Y F G M G K M A V S W H H D E N L V D R S A V A V Y S Y S C E G P E E E S E D D S H L E G R D P D I W H V G F K I S W D I E T P G L A I P L H Q G D C Y F M L D D L N A T H Q H C V L A G S Q P R F S S T H R V A E C S T G T L D Y I L Q R C Q L A L Q N V C D D V D N D D V S L K S F E P A V L K Q G E E I H N E V E F E W L R Q F W F Q G N R Y R K C T D W W C Q P M A Q L E A L W K K M E G V T N A V L H E V K R E G L P V E Q R N E I L T A I L A S L T A R Q N L R R E W H A R C Q S R I A R T L P A D Q K P E C R P Y W E K D D A S M P L P F D L T D I V S E L R G Q L L E A K P

Secondary Structure Alphabet

G: 3-turn helix (3₁₀helix)
H: α-helix
I: 𝝅-helix (5 - turn helix)
T: Hydrogen Bonded Turn
B: β-sheet
S: Bend
C: Coil (residues not present in any of the above conformations)
N: Not assigned

Download PDB Structures & DSSP Secondary Structures:

Alpha Fold Pdb Files	AF-Q9C0B1-F1.pdb
Alpha Fold Pdbx/mmCIF Files	AF-Q9C0B1-F1.cif
DSSP Secondary Structures	Q9C0B1.dssp

Diseases connected to this enzyme:

Description	Reaction	Disease Name
Associations between the FTO SNPs and type 2 diabetes, further investigation is needed to identify the causal genetic variants and potential mechanisms underlying the observed genetic associations	A:m6A	Type 2 Diabetes
Demethylation of adenosine residues in the 3′‐UTR of PGC‐1α mRNA (induced by FTO), leads to increased PGC‐1α mRNA stability and protein expression, and increased mitochondrial biogenesis, oxidative stress and tumour suppression	A:m6A	Renal cell carcinoma
m6A levels of POI patients is increased and FTO gene expression and protein levels are decreased. Thus, FTO could increase the risk of complications of POI	A:m6A	Premature ovarian insufficiency
The overexpression of FTO reduces m6A levels and increases NMDAR1 expression levels, NMDAR1, which could elevate oxidative stress and Ca2+. High expression of NMDAR1 will damage neurons and cause subsequent apoptotic death	A:m6A	Parkinson
Association between FTO SNPs and higher obesity risk, but further investigation is warranted to identify the causal genetic variants and potential mechanisms underlying the observed genetic associations	A:m6A	Obesity
Increased m6A methylation level reduces USP7 mRNA expression and reduces both the proliferation rate of lung cancer cells and the capacity of colony formation. The increased USP7 mRNA stability through FTO mediated demethylation explaines FTO oncogenic role for the growth of NSCLC cells	A:m6A	Non-small cell lung cancer
Increased m6A methylation level reduces MZF1 mRNA expression. FTO upregulation mediates MZF1 mRNA demethylation and increased MZF1 mRNA stability. This leads to an enhanced MZF1 expression, which explains the oncogenic roles of FTO in LUSCs	A:m6A	Non-small cell lung cancer
The increased m6A methylation level, in melanoma-promoting genes, PD-1 (PDCD1), CXCR4, and SOX10, promotes melanoma cells proliferation, migration and invasion in vitro and melanoma tumor growth in vivo. FTO was found to be upregulated in melanoma, suggesting a protumorigenic role. FTO higher expression is induced by metabolic stress and starvation. It was found that PD-1 (PDCD1), CXCR4, and SOX10 are regulated by FTO-mediated demethylation which blocks the YTHDF2-induced mRNA decay (tumor suppressor). Furthermore, FTO-mediated demethylation plays an important role in therapeutic resistance to anti-PD-1 immunotherapy and cell killing by IFNγ	A:m6A	Melanoma
The association between MPM and asbestos exposure is established but the mechanism is unclear. It was proposed that asbestos causes DNA damage by inducing DNA alkylation and methylation. Thus, methylation could be at the bases of the MPM onset and the characterized FTO rs9939609 polymorphism which alters its expression level, may play a role in asbestos-induced methylation and carcinogenesis	A:m6A	Malignant pleural mesothelioma
Association between SNP rs9939609 within FTO and major depressive disorder, independently from BMI	A:m6A	Major depressive disorder
Mutations found in m6A regulatory genes are associated with lower OS and EFS rates in patients with AML ( Acute myeloid Leukemia) and presence of p53 mutations.	A:m6A	Leukemia
FTO highly expressed in AML t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m6A levels in these mRNA transcripts.	A:m6A	Leukemia
FTO promotes AML progression	A:m6A	Leukemia
Loss of function mutation in FTO gene leads to leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass	A:m6A	Intellectual disability
m6A methylation protects against GSCs growth and self-renewal. FTO induced demethylation regulates GSCs growth and self-renewal, promotes tumor progression and shortens the lifespan of GSC-grafted animals.	A:m6A	Glioblastoma
FTO overexpression in GC tissues was positively correlated with GC histological differentiation, lymph node metastasis and TNM stage. It may promote GC occurrence and its abnormal expression might be associated with GC tumor progression and metastasis. Moreover,in vitro, the viability, proliferation, migration and invasion of GC cells were markedly promoted by the overexpression of FTO	A:m6A	Gastric cancer
Decreased m6A methylation level, by METTL14 downregulation or FTO upregulation, promotes the activation of oncogenic signaling pathways, such as Wnt and PI3K‐Akt and supports GC cell proliferation, migration and invasion.	A:m6A	Gastric cancer
m6A methylation of β-catenin was found to be related to chemo/radiotherapy resistance of CSCC cells. Increased levels of FTO in those cells induce a decreased methylation level in β-catenin and an increased chemo/radiotherapy resistance through the ERCC1 axis.	A:m6A	Cervical cancer
FTO is frequently overexpressed in human cervical cancer tissues and highly correlated with cervical cancer progression.Mechanistically, FTO directly interacted with E2F1 and Myc mRNAs and inhibition FTO dramatically impaired the translation of these two important oncogenes, thus suppressed cervical cancer cells’ proliferation and migration.	A:m6A	Cervical cancer
m6A demethylation in the 3' UTR of BNIP3 mRNA leads to its degradation.	A:m6A	Breast cancer
m6A levels are reduced in breast cancer samples due to a decrease in m6A methylases expression and an increase in demethylases expression; expression levels of METTL3, METTL14, WTAP and FTO were correlated with poor survival and cancer progression; m6A higher levels suppress cancer cell viability, inhibit MDA-MB-231 colony-formation abilities and cell migratory abilities.Expression levels of writers and readers differes according to the subtype of breast cancer ( luminal A/B vs. triple negative).	A:m6A	Breast cancer
Structural brain atrophy in carriers of the FTO risk allele (SNP rs9939609) is identified in healthy elderly subjects . Those carrying at least one copy of the risk allele showed brain tissue deficits in the frontal and the occipital lobes, areas that are also associated with volume reductions in subjects with higher BMI.	A:m6A	Brain atrophy
Involvement of the FTO SNP rs8050136 in modulating the risk for ADHD	A:m6A	Attention-deficit/hyperactivity disorder (ADHD)
FTO regulates the phosphorylation of Tau in a mTOR-dependent manner by targeting and reducing the mRNA level of TSC1.	A:m6A	Alzheimer
m6A methyltransferase METTL3 is elevated and the m6A demethylase FTO is decreased in AD mice. The related pathways and genes predicted the potential roles of the differentially expressed m6A methylation RNA in AD.	A:m6A	Alzheimer

Publications:

Title	Authors	Journal	Details	PubMed Id	DOI
FTO-mediated formation of N(6)-hydroxymethyladenosine and N(6)-formyladenosine in mammalian RNA.	Fu Y, Jia G, Pang X, Wang RN, Wang X, Li CJ, Smemo S, Dai Q, Bailey KA, Nobrega MA, Han KL, Cui Q, He C...	Nat Commun	[details]	23653210	-
N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.	Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C...	Nat Chem Biol	[details]	22002720	-
Crystal structure of the FTO protein reveals basis for its substrate specificity.	Han Z, Niu T, Chang J, Lei X, Zhao M, Wang Q, Cheng W, Wang J, Feng Y, Chai J...	Nature	[details]	20376003	-
Molecular biology. Internal mRNA methylation finally finds functions.	Nilsen TW...	Science	[details]	24626918	-
FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.	Zhao X, Yang Y, Sun BF, Shi Y, Yang X, Xiao W, Hao YJ, Ping XL, Chen YS, Wang WJ, Jin KX, Wang X, Huang CM, Fu Y, Ge XM, Song SH, Jeong HS, Yanagisawa H, Niu Y, Jia GF, Wu W, Tong WM, Okamoto A, He C, Rendtlew Danielsen JM, Wang XJ, Yang YG...	Cell Res	[details]	25412662	-

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