التفاصيل البيبلوغرافية
| العنوان: |
Structural basis for product specificities of MLL family methyltransferases. |
| المؤلفون: |
Li, Yanjing1,2 (AUTHOR), Zhao, Lijie1,3 (AUTHOR), Zhang, Yuebin1,4 (AUTHOR), Wu, Ping1,5 (AUTHOR), Xu, Ying1 (AUTHOR), Mencius, Jun2 (AUTHOR), Zheng, Yongxin2 (AUTHOR), Wang, Xiaoman1,3 (AUTHOR), Xu, Wancheng1,3 (AUTHOR), Huang, Naizhe1,3 (AUTHOR), Ye, Xianwen6 (AUTHOR), Lei, Ming7 (AUTHOR), Shi, Pan8 (AUTHOR), Tian, Changlin8 (AUTHOR), Peng, Chao1,5 (AUTHOR) pengchao@sari.ac.cn, Li, Guohui1,4 (AUTHOR) ghli@dicp.ac.cn, Liu, Zhijun1,5 (AUTHOR) liuzhijun@sari.ac.cn, Quan, Shu1,2 (AUTHOR) shuquan@ecust.edu.cn, Chen, Yong1,3,6 (AUTHOR) yongchen@sibcb.ac.cn |
| المصدر: |
Molecular Cell. Oct2022, Vol. 82 Issue 20, p3810-3810. 1p. |
| مصطلحات موضوعية: |
*MOLECULAR dynamics, *HISTONE methyltransferases, *HISTONE methylation, *NUCLEAR magnetic resonance, *HISTONES |
| مستخلص: |
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. [Display omitted] • MLL family methyltransferases possess distinct product specificities • Dynamics of the "F/Y switch" residues fine-tune the product specificity • Sequence variation in SET-N and SET-C interface affects the "F/Y switch" dynamics • The modified "F/Y switch" rule is applicable for most SET domain methyltransferases Li et al. establish a general criterion to define product specificity by comparing methylation rates of each step, enabling decoding the multifaceted product specificity of MLL family methyltransferases. They propose a modified "F/Y switch" rule applicable for most SET domain methyltransferases and provide a deeper understanding of dynamic histone methylation. [ABSTRACT FROM AUTHOR] |
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