Structural and Biochemical Insights into MLL1 Core Complex Assembly
Structural and Biochemical Insights into MLL1 Core Complex Assembly
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DOI：
10.1016/j.str.2010.09.022
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发表时间：
2011-01-12
期刊：
影响因子：
5.7
通讯作者：
Couture, Jean-Francois
中科院分区：
文献类型：
--
作者：
Avdic, Vanja;Zhang, Pamela;Couture, Jean-Francois
组蛋白H3 Lys-4甲基化主要由甲基转移酶家族催化，其酶活性取决于它们与由WDR5，RBBP5和ASH2L组成的三元组合物的相互作用。在这里，我们报告说，RBBP5的50个残留物将ASH2L C末端域桥接到WDR5。 WDR5在带有RBBP5和MLL1的三元络合物中的晶体结构表明，两种蛋白质都结合了位于WDR5β-螺旋桨域对面的肽结合裂口。 RBBP5在WDR5上的两个叶片的连接形成的V形裂口内参与了几种氢键和范德华触点。 WDR5 V形裂口和RBBP5残基的突变分析表明，RBBP5和WDR5之间的相互作用对于刺激MLL1甲基转移酶活性很重要。总体而言，这项研究提供了WDR5-RBBP5子复合物形成的结构基础，并进一步强调了WDR5在脚手架中的关键作用。
Histone H3 Lys-4 methylation is predominantly catalyzed by a family of methyltransferases whose enzymatic activity depends on their interaction with a three-subunit complex composed of WDR5, RbBP5, and Ash2L. Here, we report that a segment of 50 residues of RbBP5 bridges the Ash2L C-terminal domain to WDR5. The crystal structure of WDR5 in ternary complex with RbBP5 and MLL1 reveals that both proteins binds peptide-binding clefts located on opposite sides of WDR5's beta-propeller domain. RbBP5 engages in several hydrogen bonds and van der Waals contacts within a V-shaped cleft formed by the junction of two blades on WDR5. Mutational analyses of both the WDR5 V-shaped cleft and RbBP5 residues reveal that the interactions between RbBP5 and WDR5 are important for the stimulation of MLL1 methyltransferase activity. Overall, this study provides the structural basis underlying the formation of the WDR5-RbBP5 subcomplex and further highlight the crucial role of WDR5 in scaffolding the MLL1 core complex.