Henry Wellcome Laboratories of Structural Biology, Department of Biochemistry, University of Leicester, UK.
Mol Cell. 2013 Jul 11;51(1):57-67. doi: 10.1016/j.molcel.2013.05.020. Epub 2013 Jun 20.
Class I histone deacetylases (HDAC1, HDAC2, and HDAC3) are recruited by cognate corepressor proteins into specific transcriptional repression complexes that target HDAC activity to chromatin resulting in chromatin condensation and transcriptional silencing. We previously reported the structure of HDAC3 in complex with the SMRT corepressor. This structure revealed the presence of inositol-tetraphosphate [Ins(1,4,5,6)P4] at the interface of the two proteins. It was previously unclear whether the role of Ins(1,4,5,6)P4 is to act as a structural cofactor or a regulator of HDAC3 activity. Here we report the structure of HDAC1 in complex with MTA1 from the NuRD complex. The ELM2-SANT domains from MTA1 wrap completely around HDAC1 occupying both sides of the active site such that the adjacent BAH domain is ideally positioned to recruit nucleosomes to the active site of the enzyme. Functional assays of both the HDAC1 and HDAC3 complexes reveal that Ins(1,4,5,6)P4 is a bona fide conserved regulator of class I HDAC complexes.
I 类组蛋白去乙酰化酶（HDAC1、HDAC2 和 HDAC3）通过同源核心抑制蛋白募集到特定的转录抑制复合物中，将 HDAC 活性靶向染色质，导致染色质凝聚和转录沉默。我们之前报道了 HDAC3 与 SMRT 核心抑制蛋白复合物的结构。该结构揭示了两种蛋白质界面处存在肌醇四磷酸[Ins(1,4,5,6)P4]。此前尚不清楚 Ins(1,4,5,6)P4 的作用是作为结构辅助因子还是 HDAC3 活性的调节剂。在这里，我们报告了 NuRD 复合物中 MTA1 与 HDAC1 复合物的结构。MTA1 的 ELM2-SANT 结构域完全包裹 HDAC1，占据活性位点的两侧，使得相邻的 BAH 结构域能够将核小体理想地募集到酶的活性位点。对 HDAC1 和 HDAC3 复合物的功能测定表明，Ins(1,4,5,6)P4 是 I 类 HDAC 复合物的真正保守调节剂。
