Structural insights into FTO's catalytic mechanism for the demethylation of multiple RNA substrates
文献类型：期刊论文
| 作者 | Yan, Ning3; Amu, Gubu3; Zhang, Liang2; Tang, Xinjing3; Jia, Guifang1,4; Zhang, Xiao1; Wei, Lian-Huan1; Wang, Yuxin2; Xiao, Yu1; Liu, Jun1 |
| 刊名 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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| 出版日期 | 2019-02-19 |
| 卷号 | 116期号:8页码:2919-2924 |
| 关键词 | RNA modification RNA demethylase FTO enzyme catalysis structure |
| ISSN号 | 0027-8424 |
| DOI | 10.1073/pnas.1820574116 |
| 通讯作者 | Zhang, Liang(liangzhang2014@sjtu.edu.cn) ; Jia, Guifang(guifangjia@pku.edu.cn) |
| 英文摘要 | FTO demethylates internal N-6-methyladenosine (m(6)A) and N-6,2'-O-dimethyladenosine (m(6)A(m); at the cap + 1 position) in mRNA, m(6)A and m(6)A(m) 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 ((6)mA), 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)A(m). Considering that (6)mA, m(6)A, and m(6)A(m) all share the same nucleobase, we present a crystal structure of human FTO bound to (6)mA-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 andm(6)A(m) 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. |
| WOS关键词 | M(6)A RNA ; GENE ; METHYLATION ; OBESITY ; MOUSE ; DNA ; CHILDHOOD ; REVEALS ; MASS ; ALKB |
| 资助项目 | National Basic Research Program of China[2017YFA0505201] ; National Natural Science Foundation of China[21722802] ; National Natural Science Foundation of China[21820102008] ; National Natural Science Foundation of China[21432002] ; National Natural Science Foundation of China[21572133] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000459074400027 |
| 出版者 | NATL ACAD SCIENCES |
| 资助机构 | National Basic Research Program of China ; National Basic Research Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Basic Research Program of China ; National Basic Research Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Basic Research Program of China ; National Basic Research Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Basic Research Program of China ; National Basic Research Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China |
| 源URL | [http://cas-ir.dicp.ac.cn/handle/321008/165988]  |
| 专题 | 大连化学物理研究所_中国科学院大连化学物理研究所 |
| 通讯作者 | Zhang, Liang; Jia, Guifang |
| 作者单位 | 1.Peking Univ, Key Lab Bioorgan Chem & Mol Engn, Synthet & Funct Biomol Ctr,Minist Educ, Beijing Natl Lab Mol Sci,Coll Chem & Mol Engn, Beijing 100871, Peoples R China 2.Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol & Chem Biol, Shanghai 200025, Peoples R China 3.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China 4.Peking Univ, Beijing Adv Innovat Ctr Genom, Beijing 100871, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yan, Ning,Amu, Gubu,Zhang, Liang,et al. Structural insights into FTO's catalytic mechanism for the demethylation of multiple RNA substrates[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2019,116(8):2919-2924. |
| APA | Yan, Ning.,Amu, Gubu.,Zhang, Liang.,Tang, Xinjing.,Jia, Guifang.,...&Zhang, Wei.(2019).Structural insights into FTO's catalytic mechanism for the demethylation of multiple RNA substrates.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,116(8),2919-2924. |
| MLA | Yan, Ning,et al."Structural insights into FTO's catalytic mechanism for the demethylation of multiple RNA substrates".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116.8(2019):2919-2924. |
入库方式： OAI收割
来源：大连化学物理研究所
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