Structural basis for product specificities of MLL family methyltransferases

Yanjing Li; Lijie Zhao; Yuebin Zhang; Ping Wu; Ying Xu; Jun Mencius; Yongxin Zheng; Xiaoman Wang; Wancheng Xu; Naizhe Huang; Xianwen Ye; Ming Lei; Pan Shi; Changlin Tian; Chao Peng; Guohui Li; Zhijun Liu; Shu Quan; Yong Chen

doi:10.1016/j.molcel.2022.08.022

Structural basis for product specificities of MLL family methyltransferases

Mol Cell. 2022 Oct 20;82(20):3810-3825.e8. doi: 10.1016/j.molcel.2022.08.022. Epub 2022 Sep 14.

Authors

Yanjing Li¹, Lijie Zhao², Yuebin Zhang³, Ping Wu⁴, Ying Xu⁵, Jun Mencius⁶, Yongxin Zheng⁶, Xiaoman Wang², Wancheng Xu², Naizhe Huang², Xianwen Ye⁷, Ming Lei⁸, Pan Shi⁹, Changlin Tian⁹, Chao Peng¹⁰, Guohui Li¹¹, Zhijun Liu¹², Shu Quan¹³, Yong Chen¹⁴

Affiliations

¹ State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing, Shanghai 200237, China.
² State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
⁴ National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China.
⁵ State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
⁶ State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing, Shanghai 200237, China.
⁷ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁸ Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁹ The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei 230026, China.
¹⁰ National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China. Electronic address: pengchao@sari.ac.cn.
¹¹ Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China. Electronic address: ghli@dicp.ac.cn.
¹² National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China. Electronic address: liuzhijun@sari.ac.cn.
¹³ State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing, Shanghai 200237, China. Electronic address: shuquan@ecust.edu.cn.
¹⁴ State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: yongchen@sibcb.ac.cn.

PMID: 36108631
DOI: 10.1016/j.molcel.2022.08.022

Abstract

Human mixed-lineage leukemia (MLL) family methyltransferases methylate histone H3 lysine 4 to different methylation states (me1/me2/me3) with distinct functional outputs, but the mechanism underlying the different product specificities of MLL proteins remains unclear. Here, we develop methodologies to quantitatively measure the methylation rate difference between mono-, di-, and tri-methylation steps and demonstrate that MLL proteins possess distinct product specificities in the context of the minimum MLL-RBBP5-ASH2L complex. Comparative structural analyses of MLL complexes by X-ray crystal structures, fluorine-19 nuclear magnetic resonance, and molecular dynamics simulations reveal that the dynamics of two conserved tyrosine residues at the "F/Y (phenylalanine/tyrosine) switch" positions fine-tune the product specificity. The variation in the intramolecular interaction between SET-N and SET-C affects the F/Y switch dynamics, thus determining the product specificities of MLL proteins. These results indicate a modified F/Y switch rule applicable for most SET domain methyltransferases and implicate the functional divergence of MLL proteins.

Keywords: F/Y switch; MLL family methyltransferases; SET domain; crystal structure; histone methylation; mass spectrometry; product specificity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Fluorine / metabolism
Histone-Lysine N-Methyltransferase* / metabolism
Histones / metabolism
Humans
Leukemia*
Lysine / metabolism
Methyltransferases / genetics
Methyltransferases / metabolism
Myeloid-Lymphoid Leukemia Protein / metabolism
Phenylalanine
Tyrosine

Substances

Histone-Lysine N-Methyltransferase
Histones
Methyltransferases
Lysine
Fluorine
Myeloid-Lymphoid Leukemia Protein
Tyrosine
Phenylalanine