5zmd
Crystal structure of FTO in complex with m6dA modified ssDNA
Structural highlights
DiseaseFTO_HUMAN Defects in FTO are the cause of growth retardation developmental delay coarse facies and early death (GDFD) [MIM:612938. A severe polymalformation syndrome characterized by postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism. In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate are observed. Early death occurs by the age of 3 years.[1] FunctionFTO_HUMAN Dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation. Has highest activity towards single-stranded RNA containing 3-methyluracil, followed by single-stranded DNA containing 3-methylthymine. Has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine. Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. Requires molecular oxygen, alpha-ketoglutarate and iron. Contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. Contributes to the regulation of body size and body fat accumulation.[2] [3] Publication Abstract from PubMedFTO demethylates internal N (6)-methyladenosine (m(6)A) and N (6),2'-O-dimethyladenosine (m(6)Am; at the cap +1 position) in mRNA, m(6)A and m(6)Am in snRNA, and N (1)-methyladenosine (m(1)A) in tRNA in vivo, and in vitro evidence supports that it can also demethylate N (6)-methyldeoxyadenosine (6mA), 3-methylthymine (3mT), and 3-methyluracil (m(3)U). However, it remains unclear how FTO variously recognizes and catalyzes these diverse substrates. Here we demonstrate-in vitro and in vivo-that FTO has extensive demethylation enzymatic activity on both internal m(6)A and cap m(6)Am Considering that 6mA, m(6)A, and m(6)Am all share the same nucleobase, we present a crystal structure of human FTO bound to 6mA-modified ssDNA, revealing the molecular basis of the catalytic demethylation of FTO toward multiple RNA substrates. We discovered that (i) N (6)-methyladenine is the most favorable nucleobase substrate of FTO, (ii) FTO displays the same demethylation activity toward internal m(6)A and m(6)Am in the same RNA sequence, suggesting that the substrate specificity of FTO primarily results from the interaction of residues in the catalytic pocket with the nucleobase (rather than the ribose ring), and (iii) the sequence and the tertiary structure of RNA can affect the catalytic activity of FTO. Our findings provide a structural basis for understanding the catalytic mechanism through which FTO demethylates its multiple substrates and pave the way forward for the structure-guided design of selective chemicals for functional studies and potential therapeutic applications. Structural insights into FTO's catalytic mechanism for the demethylation of multiple RNA substrates.,Zhang X, Wei LH, Wang Y, Xiao Y, Liu J, Zhang W, Yan N, Amu G, Tang X, Zhang L, Jia G Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2919-2924. doi:, 10.1073/pnas.1820574116. Epub 2019 Feb 4. PMID:30718435[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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