Structural Basis for the Requirement of Additional Factors for MLL1 SET Domain Activity and Recognition of Epigenetic Marks
Structural Basis for the Requirement of Additional Factors for MLL1 SET Domain Activity and Recognition of Epigenetic Marks
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DOI：
10.1016/j.molcel.2008.12.029
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发表时间：
2009-01-30
期刊：
影响因子：
16
通讯作者：
Wilson, Jon R.
中科院分区：
文献类型：
--
作者：
Southall, Stacey M.;Wong, Poon-Sheng;Wilson, Jon R.
混合系白血病蛋白MLL1是一种转录调节蛋白，在早期发育和造血过程中发挥重要作用。MLL1的生物学功能是通过其羧基末端的组蛋白H3K4甲基转移酶活性来实现的。我们测定了MLL1 SET结构域与辅因子产物ADOHcy和一个组蛋白H3肽的络合物的晶体结构。这种结构表明，为了形成有序的活性部位，SET结构域的高度可变但必不可少的成分必须被重新定位。为了验证这一想法，我们比较了MLL复合体成员的添加对甲基转移酶活性的影响，结果表明RbBP5和Ash2L都能刺激活性，但WDR5不能。此外，我们还确定了翻译后修饰对靶赖氨酸下游和上游组蛋白H3残基的影响，并对H3T3磷酸化和H3K9乙酰化调节活性的原因提供了结构上的解释。
The mixed-lineage leukemia protein MLL1 is a transcriptional regulator with an essential role in early development and hematopoiesis. The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain. We have determined the crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide. This structure indicates that, in order to form a well ordered active site, a highly variable but essential component of the SET domain must be repositioned. To test this idea, we compared the effect of the addition of MLL complex members on methyltransferase activity and show that both RbBP5 and Ash2L but not Wdr5 stimulate activity. Additionally, we have determined the effect of posttranslational modifications on histone H3 residues downstream and upstream from the target lysine and provide a structural explanation for why H3T3 phosphorylation and H3K9 acetylation regulate activity.