Crystal structure of the fat mass and obesity associated (FTO) protein reveals basis for its substrate specificity
Classification:
OXIDOREDUCTASE
Technique:
X-Ray Diffraction
Resolution:
2.5
R value free:
0.285
R value observed:
R value work:
0.239
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.
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.
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...