2. Academic Validation
  3. Crystal structure of human METTL6, the m3C methyltransferase

Crystal structure of human METTL6, the m3C methyltransferase

  • Commun Biol. 2021 Dec 3;4(1):1361. doi: 10.1038/s42003-021-02890-9.
Ran Chen 1 2,  Jie Zhou 1,  Ling Liu 1,  Xue-Ling Mao 3,  Xiaolong Zhou 3,  Wei Xie 4
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong, 510006, People's Republic of China.
  • 2 Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, Innovation Academy of South China Sea Ecology and Environmental Engineering, South China Sea Institute of Oceanology, Chinese Academy of Sciences, No. 1119, Haibin Road, Nansha District, Guangzhou, 511458, People's Republic of China.
  • 3 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, People's Republic of China.
  • 4 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong, 510006, People's Republic of China. xiewei6@mail.sysu.edu.cn.
PMID: 34862464 DOI: 10.1038/s42003-021-02890-9
Abstract

In tRNA, the epigenetic m3C modification at position 32 in the anticodon loop is highly conserved in eukaryotes, which maintains the folding and basepairing functions of the anticodon. However, the responsible Enzymes METTL2 and METTL6 were identified only in recent years. The loss of human METTL6 (hMETTL6) affects the translational process and proteostasis in cells, while in mESCs cells, it leads to defective pluripotency potential. Despite its important functions, the catalytic mechanism of the C32 methylation by this Enzyme is poorly understood. Here we present the 1.9 Å high-resolution crystal structure of hMETTL6 bound by SAH. The key residues interacting with the ligand were identified and their roles were confirmed by ITC. We generated a docking model for the hMETTL6-SAH-CMP ternary complex. Interestingly, the CMP molecule binds into a cavity in a positive patch with the base ring pointing to the inside, suggesting a flipped-base mechanism for methylation. We further generated a model for the quaternary complex with tRNASer as a component, which reasonably explained the biochemical behaviors of hMETTL6. Taken together, our crystallographic and biochemical studies provide important insight into the molecular recognition mechanism by METTL6 and may aid in the METTL-based rational drug design in the future.

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