Structural basis for product specificities of MLL family methyltransferases
Structural basis for product specificities of MLL family methyltransferases
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MLL 家族甲基转移酶产品特异性的结构基础
DOI：
10.1016/j.molcel.2022.08.022
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发表时间：
2022-10-20
期刊：
影响因子：
16
通讯作者：
Chen, Yong
中科院分区：
文献类型：
--
作者：
Li, Yanjing;Zhao, Lijie;Chen, Yong
人类混合系白血病（MLL）家族甲基转移酶将组蛋白H3赖氨酸4甲基化为具有不同功能输出的不同甲基化状态（me 1/me 2/me 3），但MLL蛋白不同产物特异性的潜在机制仍不清楚。在这里，我们开发的方法来定量测量之间的甲基化率差异的单，双，和三甲基化步骤，并证明MLL蛋白具有不同的产品特异性的上下文中的最小MLL-RBBP 5-ASH 2L复合物。通过X射线晶体结构、氟-19核磁共振和分子动力学模拟对MLL复合物进行的比较结构分析表明，在“F/Y（苯丙氨酸/酪氨酸）开关“位置处的两个保守酪氨酸残基的动力学微调了产物特异性。SET-N和SET-C之间的分子内相互作用的变化影响F/Y转换动力学，从而确定MLL蛋白的产物特异性。这些结果表明，修改后的F/Y开关规则适用于大多数SET结构域甲基转移酶，并暗示MLL蛋白的功能分歧。
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.