A non-active-site SET domain surface crucial for the interaction of MLL1 and the RbBP5/Ash2L heterodimer within MLL family core complexes.
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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DOI：
10.1016/j.jmb.2014.03.011
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发表时间：
2014-06-12
影响因子：
5.6
通讯作者：
Cosgrove MS
中科院分区：
文献类型：
--
作者：
Shinsky SA;Hu M;Vought VE;Ng SB;Bamshad MJ;Shendure J;Cosgrove MS
混合谱系白血病-1（MLL 1）酶是一种组蛋白H3赖氨酸4（H3 K4）单甲基转移酶，并已成为了解人类SET 1酶家族（包括MLL 1 -4和SET 1d 1a，b）作用机制的范式。H3 K4的二甲基化需要包括WDR 5、RbBP 5、Ash 2L和DPY-30（WRAD）的亚复合物，其结合到每个SET 1家族成员，形成多个赖氨酸甲基化所需的最小核心复合物。我们最近证明，WRAD是一种新的组蛋白甲基转移酶，优先催化H3 K4二甲基化的方式是依赖于一个未知的非活性位点表面从MLL 1 SET域。最近的基因组测序研究已经确定了一些人类疾病相关的错义突变，定位于几个MLL家族成员的SET结构域。在这项研究中，我们将许多这些突变映射到SET结构域的三维结构上，并注意到MLL 2（KMT 2D，ALR，MLL 4）相关的Kabuki综合征（KS）错义突变的一个子集映射到一个共同的溶剂暴露表面，预计不会改变酶活性。我们将这些突变引入MLL 1 SET结构域，并观察到所有突变都有MLL 1核心复合物的H3 K4二甲基化缺陷，这与MLL 1与WRAD或RbBP 5-Ash 2L异二聚体相互作用的能力丧失有关。我们的研究结果表明，氨基酸从这个表面，我们称之为歌舞伎相互作用的表面或（KIS），是必需的SET 1家族核心复合物内的第二个活性位点的形成。
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 MLL1–4, and SET1d1a,b. Dimethylation of H3K4 requires a sub-complex including WDR5, RbBP5, Ash2L, and DPY-30 (WRAD), 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 (KS) 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.
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