Structural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4

Qiang Luo, Jiezhen Mo, Hao Chen, Zetao Hu, Baihui Wang, Jiabing Wu, Ziyu Liang, Wenhao Xie, Kangxi Du, Maolin Peng, Yingping Li, Tianyang Li, Yangyi Zhang, Xiaoyan Shi, Wen-Hui Shen, Yang Shi (), Aiwu Dong (), Hailin Wang () and Jinbiao Ma ()
Additional contact information
Qiang Luo: Fudan University
Jiezhen Mo: University of Chinese Academy of Sciences
Hao Chen: Southern University of Science and Technology
Zetao Hu: Fudan University
Baihui Wang: Fudan University
Jiabing Wu: Fudan University
Ziyu Liang: University of Chinese Academy of Sciences
Wenhao Xie: Fudan University
Kangxi Du: Fudan University
Maolin Peng: Fudan University
Yingping Li: Fudan University
Tianyang Li: Fudan University
Yangyi Zhang: Southern University of Science and Technology
Xiaoyan Shi: Southern University of Science and Technology
Wen-Hui Shen: Fudan University
Yang Shi: Oxford University
Aiwu Dong: Fudan University
Hailin Wang: University of Chinese Academy of Sciences
Jinbiao Ma: Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract METTL4 belongs to a subclade of MT-A70 family members of methyltransferase (MTase) proteins shown to mediate N6-adenosine methylation for both RNA and DNA in diverse eukaryotes. Here, we report that Arabidopsis METTL4 functions as U2 snRNA MTase for N6−2’-O-dimethyladenosine (m6Am) in vivo that regulates flowering time, and specifically catalyzes N6-methylation of 2’-O-methyladenosine (Am) within a single-stranded RNA in vitro. The apo structures of full-length Arabidopsis METTL4 bound to S-adenosyl-L-methionine (SAM) and the complex structure with an Am-containing RNA substrate, combined with mutagenesis and in vitro enzymatic assays, uncover a preformed L-shaped, positively-charged cavity surrounded by four loops for substrate binding and a catalytic center composed of conserved residues for specific Am nucleotide recognition and N6-methylation activity. Structural comparison of METTL4 with the mRNA m6A enzyme METTL3/METTL14 heterodimer and modeling analysis suggest a catalytic mechanism for N6-adenosine methylation by METTL4, which may be shared among MT-A70 family members.

Date: 2022
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DOI: 10.1038/s41467-022-33277-x

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