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结构洞察 RSC 染色质重塑复合物的组装和功能。

Structural insights into assembly and function of the RSC chromatin remodeling complex.

机构信息

Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.

Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

出版信息

Nat Struct Mol Biol. 2021 Jan;28(1):71-80. doi: 10.1038/s41594-020-00528-8. Epub 2020 Dec 7.

DOI:10.1038/s41594-020-00528-8
PMID:33288924
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7855068/
Abstract

SWI/SNF chromatin remodelers modify the position and spacing of nucleosomes and, in humans, are linked to cancer. To provide insights into the assembly and regulation of this protein family, we focused on a subcomplex of the Saccharomyces cerevisiae RSC comprising its ATPase (Sth1), the essential actin-related proteins (ARPs) Arp7 and Arp9 and the ARP-binding protein Rtt102. Cryo-EM and biochemical analyses of this subcomplex shows that ARP binding induces a helical conformation in the helicase-SANT-associated (HSA) domain of Sth1. Surprisingly, the ARP module is rotated 120° relative to the full RSC about a pivot point previously identified as a regulatory hub in Sth1, suggesting that large conformational changes are part of Sth1 regulation and RSC assembly. We also show that a conserved interaction between Sth1 and the nucleosome acidic patch enhances remodeling. As some cancer-associated mutations dysregulate rather than inactivate SWI/SNF remodelers, our insights into RSC complex regulation advance a mechanistic understanding of chromatin remodeling in disease states.

摘要

SWI/SNF 染色质重塑酶改变核小体的位置和间距，在人类中与癌症有关。为了深入了解这个蛋白质家族的组装和调节机制，我们专注于酿酒酵母 RSC 的一个亚基复合物，该亚基复合物包含其 ATP 酶（Sth1）、必需的肌动蛋白相关蛋白（ARPs）Arp7 和 Arp9 以及 ARP 结合蛋白 Rtt102。该亚基复合物的冷冻电镜和生化分析表明，ARP 结合诱导 Sth1 的螺旋酶-SANT 相关（HSA）结构域形成螺旋构象。令人惊讶的是，相对于完整的 RSC，ARP 模块相对于先前鉴定为 Sth1 中调节枢纽的支点旋转了 120°，这表明大的构象变化是 Sth1 调节和 RSC 组装的一部分。我们还表明，Sth1 和核小体酸性斑之间的保守相互作用增强了重塑。由于一些与癌症相关的突变会使 SWI/SNF 重塑酶失活而非失活，因此我们对 RSC 复合物调节的深入了解推进了对疾病状态下染色质重塑的机制理解。

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