Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, USA.
Nature. 2020 Mar;579(7799):452-455. doi: 10.1038/s41586-020-2087-1. Epub 2020 Mar 11.
The chromatin-remodelling complex SWI/SNF is highly conserved and has critical roles in various cellular processes, including transcription and DNA-damage repair. It hydrolyses ATP to remodel chromatin structure by sliding and evicting histone octamers, creating DNA regions that become accessible to other essential factors. However, our mechanistic understanding of the remodelling activity is hindered by the lack of a high-resolution structure of complexes from this family. Here we report the cryo-electron microscopy structure of Saccharomyces cerevisiae SWI/SNF bound to a nucleosome, at near-atomic resolution. In the structure, the actin-related protein (Arp) module is sandwiched between the ATPase and the rest of the complex, with the Snf2 helicase-SANT associated (HSA) domain connecting all modules. The body contains an assembly scaffold composed of conserved subunits Snf12 (also known as SMARCD or BAF60), Snf5 (also known as SMARCB1, BAF47 or INI1) and an asymmetric dimer of Swi3 (also known as SMARCC, BAF155 or BAF170). Another conserved subunit, Swi1 (also known as ARID1 or BAF250), resides in the core of SWI/SNF, acting as a molecular hub. We also observed interactions between Snf5 and the histones at the acidic patch, which could serve as an anchor during active DNA translocation. Our structure enables us to map and rationalize a subset of cancer-related mutations in the human SWI/SNF complex and to propose a model for how SWI/SNF recognizes and remodels the +1 nucleosome to generate nucleosome-depleted regions during gene activation.
染色质重塑复合物 SWI/SNF 高度保守，在多种细胞过程中发挥关键作用，包括转录和 DNA 损伤修复。它通过滑动和驱逐组蛋白八聚体来水解 ATP，重塑染色质结构，从而创建对其他必需因子可及的 DNA 区域。然而，由于缺乏来自该家族复合物的高分辨率结构，我们对重塑活性的机制理解受到阻碍。在这里，我们报告了酿酒酵母 SWI/SNF 与核小体结合的近原子分辨率冷冻电子显微镜结构。在该结构中，肌动蛋白相关蛋白（Arp）模块夹在 ATP 酶和复合物的其余部分之间，Snf2 解旋酶-SANT 相关（HSA）结构域连接所有模块。主体包含由保守亚基 Snf12（也称为 SMARCD 或 BAF60）、Snf5（也称为 SMARCB1、BAF47 或 INI1）和 Swi3（也称为 SMARCC、BAF155 或 BAF170）的不对称二聚体组成的组装支架。另一个保守的亚基 Swi1（也称为 ARID1 或 BAF250）位于 SWI/SNF 的核心，充当分子枢纽。我们还观察到 Snf5 与酸性斑处组蛋白之间的相互作用，这可能在活性 DNA 易位期间作为锚点。我们的结构使我们能够映射和合理化人类 SWI/SNF 复合物中与癌症相关的突变，并提出一个模型，说明 SWI/SNF 如何识别和重塑+1 核小体，以在基因激活过程中产生核小体耗尽区域。
