The Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK.
Nucleic Acids Res. 2020 Dec 16;48(22):12972-12982. doi: 10.1093/nar/gkaa1121.
Class I histone deacetylase complexes play essential roles in many nuclear processes. Whilst they contain a common catalytic subunit, they have diverse modes of action determined by associated factors in the distinct complexes. The deacetylase module from the NuRD complex contains three protein domains that control the recruitment of chromatin to the deacetylase enzyme, HDAC1/2. Using biochemical approaches and cryo-electron microscopy, we have determined how three chromatin-binding domains (MTA1-BAH, MBD2/3 and RBBP4/7) are assembled in relation to the core complex so as to facilitate interaction of the complex with the genome. We observe a striking arrangement of the BAH domains suggesting a potential mechanism for binding to di-nucleosomes. We also find that the WD40 domains from RBBP4 are linked to the core with surprising flexibility that is likely important for chromatin engagement. A single MBD2 protein binds asymmetrically to the dimerisation interface of the complex. This symmetry mismatch explains the stoichiometry of the complex. Finally, our structures suggest how the holo-NuRD might assemble on a di-nucleosome substrate.
I 类组蛋白去乙酰化酶复合物在许多核过程中发挥着重要作用。虽然它们含有共同的催化亚基，但由于不同复合物中相关因子的作用，它们具有不同的作用模式。NuRD 复合物的去乙酰化酶模块包含三个蛋白结构域，可控制组蛋白与去乙酰化酶酶（HDAC1/2）的募集。我们使用生化方法和冷冻电镜技术，确定了三个染色质结合结构域（MTA1-BAH、MBD2/3 和 RBBP4/7）如何相对于核心复合物组装，以促进复合物与基因组的相互作用。我们观察到 BAH 结构域的排列引人注目，表明了与二核小体结合的潜在机制。我们还发现，RBBP4 的 WD40 结构域与核心的连接具有惊人的灵活性，这可能对染色质结合很重要。单个 MBD2 蛋白不对称地结合到复合物的二聚化界面上。这种对称失配解释了复合物的化学计量。最后，我们的结构表明全酶 NuRD 如何在二核小体底物上组装。
