Insights into the Recruitment of Class IIa Histone Deacetylases (HDACs) to the SMRT/NCoR Transcriptional Repression Complex.
Insights into the Recruitment of Class IIa Histone Deacetylases (HDACs) to the SMRT/NCoR Transcriptional Repression Complex.
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DOI：
10.1074/jbc.m115.661058
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发表时间：
2015-07-17
期刊：
影响因子：
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通讯作者：
Schwabe JWR
中科院分区：
文献类型：
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作者：
Hudson GM;Watson PJ;Fairall L;Jamieson AG;Schwabe JWR
背景：IIa类组蛋白去乙酰化酶（HDAC）通过与SMRT/NCOR共阻遏物复合物结合抑制转录。结果：一个重复的肽基序介导招募IIa类HDAC的辅阻遏蛋白相互作用的活性位点附近。结论：IIa类HDAC通过简单重复的肽基序被募集到共阻遏物。意义：首次深入了解IIa类HDAC与阻遏复合物的组装。IIa类组蛋白脱乙酰酶抑制靶基因的转录。然而，它们的作用机制知之甚少，因为它们表现出非常低水平的脱乙酰酶活性。IIa类HDAC与SMRT/NCoR阻遏复合物相关，这可能至少部分地解释了它们的阻遏活性。然而，募集到辅阻遏蛋白的分子机制尚未建立。在这里，我们表明，SMRT和NCoR中存在的重复肽基序足以介导与所有IIa类HDAC（HDAC 4，5，7和9）的特异性相互作用，具有微摩尔亲和力。共有基序中的突变废除结合。HDAC 4的突变分析表明，肽在酶的活性位点附近相互作用，并且需要酶表面上的锌结合环的“闭合”构象。总之，这些发现代表了对IIa类HDAC募集至SMRT/NCoR阻遏复合物的分子机制的首次见解。
Background: Class IIa histone deacetylases (HDACs) repress transcription through association with the SMRT/NCOR co-repressor complex. Results: A repeated peptide motif mediates recruitment of class IIa HDACs to the co-repressor proteins interacting adjacent to the active site. Conclusion: Class IIa HDACs are recruited to co-repressors by a simple repeated peptide motif. Significance: First insights into the assembly of Class IIa HDACs with repression complexes. Class IIa histone deacetylases repress transcription of target genes. However, their mechanism of action is poorly understood because they exhibit very low levels of deacetylase activity. The class IIa HDACs are associated with the SMRT/NCoR repression complexes and this may, at least in part, account for their repressive activity. However, the molecular mechanism of recruitment to co-repressor proteins has yet to be established. Here we show that a repeated peptide motif present in both SMRT and NCoR is sufficient to mediate specific interaction, with micromolar affinity, with all the class IIa HDACs (HDACs 4, 5, 7, and 9). Mutations in the consensus motif abrogate binding. Mutational analysis of HDAC4 suggests that the peptide interacts in the vicinity of the active site of the enzyme and requires the “closed” conformation of the zinc-binding loop on the surface of the enzyme. Together these findings represent the first insights into the molecular mechanism of recruitment of class IIa HDACs to the SMRT/NCoR repression complexes.