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

Author

Listed:
  • Qiang Luo

    (Fudan University
    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
    Université de Strasbourg)

  • Yang Shi

    (Oxford University)

  • Aiwu Dong

    (Fudan University)

  • Hailin Wang

    (University of Chinese Academy of Sciences
    Jianghan University)

  • Jinbiao Ma

    (Fudan University)

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.

Suggested Citation

  • 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 & Ya, 2022. "Structural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33277-x
    DOI: 10.1038/s41467-022-33277-x
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    References listed on IDEAS

    as
    1. Wendan Ren & Jiuwei Lu & Mengjiang Huang & Linfeng Gao & Dongxu Li & Gang Greg Wang & Jikui Song, 2019. "Structure and regulation of ZCCHC4 in m6A-methylation of 28S rRNA," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    2. Eliza Yankova & Wesley Blackaby & Mark Albertella & Justyna Rak & Etienne Braekeleer & Georgia Tsagkogeorga & Ewa S. Pilka & Demetrios Aspris & Dan Leggate & Alan G. Hendrick & Natalie A. Webster & By, 2021. "Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia," Nature, Nature, vol. 593(7860), pages 597-601, May.
    3. Xiang Wang & Jing Feng & Yuan Xue & Zeyuan Guan & Delin Zhang & Zhu Liu & Zhou Gong & Qiang Wang & Jinbo Huang & Chun Tang & Tingting Zou & Ping Yin, 2016. "Structural basis of N6-adenosine methylation by the METTL3–METTL14 complex," Nature, Nature, vol. 534(7608), pages 575-578, June.
    4. Dan Dominissini & Sharon Moshitch-Moshkovitz & Schraga Schwartz & Mali Salmon-Divon & Lior Ungar & Sivan Osenberg & Karen Cesarkas & Jasmine Jacob-Hirsch & Ninette Amariglio & Martin Kupiec & Rotem So, 2012. "Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq," Nature, Nature, vol. 485(7397), pages 201-206, May.
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