DICP OpenIR
Structural insights into FTO's catalytic mechanism for the demethylation of multiple RNA substrates
Zhang, Xiao1; Wei, Lian-Huan1; Wang, Yuxin2; Xiao, Yu1; Liu, Jun1; Zhang, Wei1; Yan, Ning3; Amu, Gubu3; Tang, Xinjing3; Zhang, Liang2; Jia, Guifang1,4
Corresponding AuthorZhang, Liang(liangzhang2014@sjtu.edu.cn) ; Jia, Guifang(guifangjia@pku.edu.cn)
KeywordRNA modification RNA demethylase FTO enzyme catalysis structure
Source PublicationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2019-02-19
ISSN0027-8424
DOI10.1073/pnas.1820574116
Volume116Issue:8Pages:2919-2924
Funding ProjectNational 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]
Funding OrganizationNational 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
WOS SubjectMultidisciplinary Sciences
WOS Research AreaScience & Technology - Other Topics
WOS KeywordM(6)A RNA ; GENE ; METHYLATION ; OBESITY ; MOUSE ; DNA ; CHILDHOOD ; REVEALS ; MASS ; ALKB
AbstractFTO 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.
Language英语
Funding OrganizationNational 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
WOS IDWOS:000459074400027
PublisherNATL ACAD SCIENCES
Citation statistics
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/165989
Collection中国科学院大连化学物理研究所
Corresponding AuthorZhang, Liang; Jia, Guifang
Affiliation1.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
Recommended Citation
GB/T 7714
Zhang, Xiao,Wei, Lian-Huan,Wang, Yuxin,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 Zhang, Xiao.,Wei, Lian-Huan.,Wang, Yuxin.,Xiao, Yu.,Liu, Jun.,...&Jia, Guifang.(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 Zhang, Xiao,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.
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