Zhang Ying, Mittal Anshumali, Reid James, Reich Stephanie, Gamblin Steven J, Wilson Jon R
The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, UK.
Domainex, Cambridge CB4 0GH, UK.
Structure. 2015 Oct 6;23(10):1921-1933. doi: 10.1016/j.str.2015.07.018. Epub 2015 Aug 27.
Methylation of histone H3 lysine-4 is a hallmark of chromatin associated with active gene expression. The activity of H3K4-specific modification enzymes, in higher eukaryotes the MLL (or KMT2) family, is tightly regulated. The MLL family has six members, each with a specialized function. All contain a catalytic SET domain that associates with a core multiprotein complex for activation. These SET domains segregate into three classes that correlate with the arrangement of targeting domains that populate the rest of the protein. Here we show that, unlike MLL1, the MLL4 SET domain retains significant activity without the core complex. We also present the crystal structure of an inactive MLL4-tagged SET domain construct and describe conformational changes that account for MLL4 intrinsic activity. Finally, our structure explains how the MLL SET domains are able to add multiple methyl groups to the target lysine, despite having the sequence characteristics of a classical monomethylase.
组蛋白H3赖氨酸-4的甲基化是与活跃基因表达相关的染色质标志。H3K4特异性修饰酶的活性，在高等真核生物中即MLL（或KMT2）家族，受到严格调控。MLL家族有六个成员，每个成员都有特定功能。所有成员都含有一个催化性SET结构域，该结构域与一个用于激活的核心多蛋白复合物相关联。这些SET结构域分为三类，这与构成蛋白质其余部分的靶向结构域的排列相关。我们在此表明，与MLL1不同，MLL4的SET结构域在没有核心复合物的情况下仍保留显著活性。我们还展示了一个无活性的MLL4标记的SET结构域构建体的晶体结构，并描述了解释MLL4内在活性的构象变化。最后，我们的结构解释了MLL的SET结构域尽管具有经典单甲基化酶的序列特征，但如何能够向目标赖氨酸添加多个甲基基团。
