用MLL甲基转移酶进行核细胞识别和修饰的结构基础
Han Xue1, Tonghui Yao1, Mi Cao2
1State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Nature
|September 6, 2019
概括
混合血统白血病 (MLL) 蛋白质甲基化基因组H3K4,对基因调节至关重要. 冷-EM结构揭示了MLL1和MLL3复合体如何与核细胞相互作用,解释了H3K4甲基化和由基因组H2B无处不在的调节.
科学领域:
- 表观遗传学和基因调控
- 结构生物学
- 基因组修饰的分子机制
背景情况:
- 混合系白血病 (MLL) 家族的甲基转移酶对于发育和细胞过程中的转录调节至关重要.
- 对于MLL酶在核细胞上沉积H3K4甲基化标记的确切机制,特别是对基因素H2B无处不在的反应,尚不清楚.
- MLL蛋白质作为WDR5,RBBP5,ASH2L和DPY30等调节因子的复合体的一部分.
研究的目的:
- 阐明MLL1和MLL3催化模块与核细胞相互作用的结构基础.
- 了解素H2B单化 (H2BK120ub1) 如何影响MLL活性和核细胞结合.
- 揭示WDR5在MLL1和MLL3酶活性中的不同调节作用.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定高分辨率结构.
- 人类MLL1和MLL3催化模块的结构与核素核心颗粒结合.
- 核体含有未经修改的素H2B或H2BK120ub1.
主要成果:
- MLL1和MLL3复合体与核体的基因组和DNA具有广泛的相互作用,使H3K4甲基化更容易进入基因组H3尾部.
- H2BK120ub1标记直接与MLL复合体的关键组成部分RBBP5相互作用,从而指导酶-核酶关联.
- 在WDR5-RBBP5-MLL接口上的不同结构组织解释了WDR5在调节MLL1与MLL3活动中的对立作用.
结论:
- 这些发现为MLL酶在核细胞层面的调节提供了前所未有的结构洞察力.
- 这项研究强调了核细胞结构的关键作用,包括像H2BK120ub1这样的基因组修饰,以指导MLL的基因组尾部修饰.
- 通过WDR5对MLL1和MLL3的差异调节强调了表观遗传控制机制的复杂性.
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