Class I HDACs share a common mechanism of regulation by inositol phosphates.
Class I HDACs share a common mechanism of regulation by inositol phosphates.
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DOI：
10.1016/j.molcel.2013.05.020
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发表时间：
2013-07-11
期刊：
影响因子：
16
通讯作者：
Schwabe, John W. R.
中科院分区：
文献类型：
--
作者：
Millard, Christopher J.;Watson, Peter J.;Celardo, Ivana;Gordiyenko, Yuliya;Cowley, Shaun M.;Robinson, Carol V.;Fairall, Louise;Schwabe, John W. R.
I类组蛋白去乙酰化酶（HDAC1、HDAC2和HDAC3）被同源辅阻遏蛋白招募到特定的转录抑制复合物中，这些复合物将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辅阻遏蛋白复合物的结构。该结构显示在这两种蛋白质的界面处存在肌醇四磷酸[Ins(1,4,5,6)P4]。之前不清楚Ins(1,4,5,6)P4的作用是作为结构辅因子还是HDAC3活性的调节剂。在此我们报道了来自NuRD复合物的HDAC1与MTA1复合物的结构。MTA1的ELM2 - SANT结构域完全环绕HDAC1，占据活性位点的两侧，使得相邻的BAH结构域处于理想位置，可将核小体招募到酶的活性位点。对HDAC1和HDAC3复合物的功能测定表明，Ins(1,4,5,6)P4是I类HDAC复合物真正保守的调节剂。
肌醇磷酸是I类HDAC辅阻遏蛋白复合物真正的调节剂
ELM2 - SANT基序是一个保守的HDAC辅阻遏蛋白组装模块
MTA1是一个二聚体，可将两个HDAC招募到NuRD复合物中
MTA1 - BAH结构域处于可将染色质招募到HDAC活性位点的位置
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. Inositol phosphates are bona fide regulators of class I HDAC corepressor complexes The ELM2-SANT motif is a conserved HDAC corepressor assembly module MTA1 is a dimer that recruits two HDACs into the NuRD complex The MTA1-BAH domain is positioned to recruit chromatin to the HDAC active site
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