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首页> 外文期刊>Journal of Molecular Biology >A non-active-site SET domain surface crucial for the interaction of MLL1 and the RbBP5/Ash2L heterodimer within MLL family core complexes
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A non-active-site SET domain surface crucial for the interaction of MLL1 and the RbBP5/Ash2L heterodimer within MLL family core complexes

机译：非活性位点SET域表面对于MLL家族核心复合物中的MLL1和RbBP5 / Ash2L异二聚体的相互作用至关重要

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The mixed lineage leukemia-1 (MLL1) enzyme is a histone H3 lysine 4 (H3K4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human SET1 family of enzymes that include MLL1-MLL4 and SETd1a,b. Dimethylation of H3K4 requires a sub-complex including WRAD (WDR5, RbBP5, Ash2L, and DPY-30), which binds to each SET1 family member forming a minimal core complex that is required for multiple lysine methylation. We recently demonstrated that WRAD is a novel histone methyltransferase that preferentially catalyzes H3K4 dimethylation in a manner that is dependent on an unknown non-active-site surface from the MLL1 SET domain. Recent genome sequencing studies have identified a number of human disease-associated missense mutations that localize to the SET domains of several MLL family members. In this investigation, we mapped many of these mutations onto the three-dimensional structure of the SET domain and noticed that a subset of MLL2 (KMT2D, ALR, MLL4)-associated Kabuki syndrome missense mutations map to a common solvent-exposed surface that is not expected to alter enzymatic activity. We introduced these mutations into the MLL1 SET domain and observed that all are defective for H3K4 dimethylation by the MLL1 core complex, which is associated with a loss of the ability of MLL1 to interact with WRAD or with the RbBP5/Ash2L heterodimer. Our results suggest that amino acids from this surface, which we term the Kabuki interaction surface or KIS, are required for formation of a second active site within SET1 family core complexes.
机译：混合谱系白血病1（MLL1）酶是组蛋白H3赖氨酸4（H3K4）单甲基转移酶，已成为理解人类SET1酶（包括MLL1-MLL4和SETd1a，b）家族作用机理的范例。 H3K4的二甲基化需要包括WRAD（WDR5，RbBP5，Ash2L和DPY-30）的亚复合物，该复合物与每个SET1家族成员结合，形成最小的核心复合物，这是赖氨酸多甲基化所必需的。我们最近证明WRAD是一种新型的组蛋白甲基转移酶，它以依赖于MLL1 SET域中未知的非活性位点表面的方式优先催化H3K4二甲基化。最近的基因组测序研究已经确定了许多与人类疾病相关的错义突变，这些突变位于几个MLL家族成员的SET结构域。在这项研究中，我们将许多此类突变映射到SET域的三维结构上，并注意到与MLL2（KMT2D，ALR，MLL4）相关的Kabuki综合征错义突变的一个子集映射到一个常见的溶剂暴露表面，即预计不会改变酶活性。我们将这些突变引入到MLL1 SET域中，并观察到MLL1核心复合体均对H3K4二甲基化存在缺陷，这与MLL1与WRAD或RbBP5 / Ash2L异二聚体相互作用的能力丧失有关。我们的结果表明，来自该表面的氨基酸（我们称为Kabuki相互作用表面或KIS）是SET1家族核心复合物中第二个活性位点形成所必需的。

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