Volume 32, No 11, Nov 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 11, November 2022: 982-994

ORIGINAL ARTICLES

Cryo-EM structures of human m6A writer complexes

Shichen Su^1,† , Shanshan Li^2,† , Ting Deng^1,† , Minsong Gao³ , Yue Yin⁴ , Baixing Wu^1,5 , Chao Peng⁴ , Jianzhao Liu³ , Jinbiao Ma^1,* , Kaiming Zhang^2,*

¹State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Multiscale Research Institute of Complex Systems, Department of Biochemistry and Biophysics, School of Life Sciences, Fudan University, Shanghai, China
²MOE Key Laboratory for Cellular Dynamics and Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
³MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, China
⁴National Facility for Protein Science in Shanghai, Zhangjiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China
⁵Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, RNA Biomedical Institute, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
^†These authors contributed equally: Shichen Su, Shanshan Li, Ting Deng
Correspondence: Jinbiao Ma(majb@fudan.edu.cn)Kaiming Zhang(kmzhang@ustc.edu.cn)

N6-methyladenosine (m6A) is the most abundant ribonucleotide modification among eukaryotic messenger RNAs. The m6A “writer” consists of the catalytic subunit m6A-METTL complex (MAC) and the regulatory subunit m6A-METTL-associated complex (MACOM), the latter being essential for enzymatic activity. Here, we report the cryo-electron microscopy (cryo-EM) structures of MACOM at a 3.0-Å resolution, uncovering that WTAP and VIRMA form the core structure of MACOM and that ZC3H13 stretches the conformation by binding VIRMA. Furthermore, the 4.4-Å resolution cryo-EM map of the MACOM–MAC complex, combined with crosslinking mass spectrometry and GST pull-down analysis, elucidates a plausible model of the m6A writer complex, in which MACOM binds to MAC mainly through WTAP and METTL3 interactions. In combination with in vitro RNA substrate binding and m6A methyltransferase activity assays, our results illustrate the molecular basis of how MACOM assembles and interacts with MAC to form an active m6A writer complex.

https://doi.org/10.1038/s41422-022-00725-8

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