Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany.
Elife. 2020 Jun 16;9:e56178. doi: 10.7554/eLife.56178.
Chromatin remodeling plays important roles in gene regulation during development, differentiation and in disease. The chromatin remodeling enzyme CHD4 is a component of the NuRD and ChAHP complexes that are involved in gene repression. Here, we report the cryo-electron microscopy (cryo-EM) structure of CHD4 engaged with a nucleosome core particle in the presence of the non-hydrolysable ATP analogue AMP-PNP at an overall resolution of 3.1 Å. The ATPase motor of CHD4 binds and distorts nucleosomal DNA at superhelical location (SHL) +2, supporting the 'twist defect' model of chromatin remodeling. CHD4 does not induce unwrapping of terminal DNA, in contrast to its homologue Chd1, which functions in gene activation. Our structure also maps CHD4 mutations that are associated with human cancer or the intellectual disability disorder Sifrim-Hitz-Weiss syndrome.
染色质重塑在发育、分化和疾病过程中的基因调控中发挥重要作用。染色质重塑酶 CHD4 是 NuRD 和 ChAHP 复合物的一个组成部分，参与基因抑制。在这里，我们报告了 CHD4 与核小体核心颗粒在非水解型 ATP 类似物 AMP-PNP 存在下的冷冻电镜 (cryo-EM) 结构，整体分辨率为 3.1 Å。CHD4 的 ATP 酶马达在超螺旋位置 (SHL) +2 处结合并扭曲核小体 DNA，支持染色质重塑的“扭曲缺陷”模型。CHD4 不会诱导末端 DNA 的展开，这与它的同源物 Chd1 形成对比，Chd1 参与基因激活。我们的结构还映射了与人类癌症或智力残疾障碍 Sifrim-Hitz-Weiss 综合征相关的 CHD4 突变。
