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

Luo，Qiang1,2; Mo，Jiezhen3; Chen，Hao4; Hu，Zetao1; Wang，Baihui2; Wu，Jiabing2; Liang，Ziyu3; Xie，Wenhao2; Du，Kangxi2; Peng，Maolin2; Li，Yingping2; Li，Tianyang2; Zhang，Yangyi4; Shi，Xiaoyan4; Shen，Wen Hui2,5; Shi，Yang6; Dong，Aiwu2; Wang，Hailin3,7; Ma，Jinbiao1

2022-09-26

10.1038/s41467-022-33277-x

Nature communications   Impact Factor & Quartile

2041-1723

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.

SCI

English

NI Journal Papers

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National Natural Science Foundation of China["31971130","31230041","31930017"]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000861440000007

NATURE PORTFOLIO

2-s2.0-85138634310

Scopus

1.State Key Laboratory of Genetic Engineering,Collaborative Innovation Center of Genetics and Development,Department of Biochemistry and Biophysics,Institute of Plant Biology,School of Life Sciences,Fudan University,200438,China
2.State Key Laboratory of Genetic Engineering,Collaborative Innovation Center of Genetics and Development,International Associated Laboratory of CNRS-Fudan-HUNAU on Plant Epigenome Research,Department of Biochemistry and Biophysics,Institute of Plant Biology,School of Life Sciences,Fudan University,200438,China
3.State Key Laboratory of Environmental Chemistry and Ecotoxicology,Research Center for Eco-Environmental Sciences,Chinese Academy of Sciences,University of Chinese Academy of Sciences,100085,China
4.Department of Human Cell Biology and Genetics,School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
5.Institut de Biologie Moléculaire des Plantes,CNRS,Université de Strasbourg,12 rue du Général Zimmer,67084,France
6.Ludwig Institute for Cancer Research,Oxford University,Oxford,Old Road Campus Research Building ,Roosevelt Dr ,Headington,OX3 7DQ,United Kingdom
7.Institute of Environment and Health,Jianghan University,Wuhan,430056,China

Luo，Qiang,Mo，Jiezhen,Chen，Hao,et al. Structural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4[J]. Nature communications,2022,13(1).

Luo，Qiang.,Mo，Jiezhen.,Chen，Hao.,Hu，Zetao.,Wang，Baihui.,...&Ma，Jinbiao.(2022).Structural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4.Nature communications,13(1).

Luo，Qiang,et al."Structural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4".Nature communications 13.1(2022).