Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex
Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex
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DOI：
10.1073/pnas.1504021112
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发表时间：
2015-07-14
影响因子：
11.1
通讯作者：
Radhakrishnan, Ishwar
中科院分区：
文献类型：
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作者：
Clark, Michael D.;Marcum, Ryan;Radhakrishnan, Ishwar
乙酰化与染色质去凝聚和转录激活相关，但其调控组蛋白去乙酰化酶（HDAC）轴承辅阻遏复合物知之甚少。在这里，我们描述了哺乳动物Sin 3L/Rpd 3L复合物的组装机制，由Sds 3，一个保守的亚基被认为是正确组装的关键。Sds 3通过包含螺旋和相邻延伸区段的二分基序接合支架蛋白Sin 3A的HDAC相互作用结构域（HID）的球状螺旋区。sds 3不仅通过预测的卷曲螺旋基序之一，而且通过其前面的片段二聚化，形成类似于150埃长的反平行二聚体。与之前在酵母中的发现相反，Sin 3A而不是Sds 3通过与螺旋HID亚结构域相邻的高度保守片段接合而在将HDAC 1招募到复合物中起作用。在所得到的三元复合物的模型中，HDAC的两个拷贝位于远端和动态的，因为一个天然的非结构化的连接器连接的二聚化结构域和Sds 3的Sin 3A相互作用结构域;这些功能与前面描述的NuRD（核小体重塑和脱乙酰酶）复合物的静态组织形成对比。Sds 3接头具有几个保守的碱性残基，这些残基可能在序列特异性DNA结合阻遏物初始募集后通过与DNA的非特异性相互作用而在染色质上维持复合物。
Acetylation is correlated with chromatin decondensation and transcriptional activation, but its regulation by histone deacetylase (HDAC)-bearing corepressor complexes is poorly understood. Here, we describe the mechanism of assembly of the mammalian Sin3L/Rpd3L complex facilitated by Sds3, a conserved subunit deemed critical for proper assembly. Sds3 engages a globular, helical region of the HDAC interaction domain (HID) of the scaffolding protein Sin3A through a bipartite motif comprising a helix and an adjacent extended segment. Sds3 dimerizes through not only one of the predicted coiled-coil motifs but also, the segment preceding it, forming an similar to 150-angstrom-long antiparallel dimer. Contrary to previous findings in yeast, Sin3A rather than Sds3 functions in recruiting HDAC1 into the complex by engaging the latter through a highly conserved segment adjacent to the helical HID subdomain. In the resulting model for the ternary complex, the two copies of the HDACs are situated distally and dynamically because of a natively unstructured linker connecting the dimerization domain and the Sin3A interaction domain of Sds3; these features contrast with the static organization described previously for the NuRD (nucleosome remodeling and deacetylase) complex. The Sds3 linker features several conserved basic residues that could potentially maintain the complex on chromatin by nonspecific interactions with DNA after initial recruitment by sequence-specific DNA-binding repressors.