人类核体结合BAF复合物的结构
Shuang He1,2, Zihan Wu1,2, Yuan Tian1,2
1Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai 200032, China.
Science (New York, N.Y.)
|February 1, 2020
概括
这项研究揭示了与核细胞结合的人类BRG1/BRM相关因子 (BAF) 复合物的结构. 这种染色体改造器
科学领域:
- 分子生物学
- 结构生物学
- 生物化学
背景情况:
- 哺乳动物的SWI/SNF复合体,包括BRG1/BRM相关因子 (BAF) 和多相关 BAF (PBAF),是染色质结构和基因转录的关键调节剂.
- 功能障碍的SWI/SNF复合体,特别是BAF,由于其子单元的突变,与各种人类癌症有关.
- 了解BAF-核酶体相互作用的结构基础对于解读其在细胞过程和疾病中的作用至关重要.
研究的目的:
- 阐明与核体结合的人类BAF复合体的高分辨率结构.
- 为BAF复合体的子单元组织和核细胞识别机制提供详细的见解.
- 确定BAF子单元与核体之间的关键相互作用,特别关注与癌症相关的突变.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 以3. 7安格斯特罗姆分辨率确定人类BAF核细胞组的结构.
- 进行了生物化学和结构分析,以描述BAF子单元与核细胞DNA和基因组之间的相互作用.
主要成果:
- 冷-EM结构显示核体位于BAF复合体的基和腺三酶 (ATPase) 模块之间,由与行为蛋白相关的蛋白质 (ARP) 模块连接在一起.
- 该ATPase电机位于核体DNA附近,在ATP水解时促进DNA沿核体转移.
- SMARCB1子单元的C端螺旋与细胞核上的酸性补丁相互作用,这种区域在癌症中经常发生突变.
- 富含AT互动域的蛋白1A (ARID1A) 和SMARCC分别构成了BAF基模块的结构核心和支架.
结论:
- 这项研究提供了人类BAF复合体与核细胞相互作用的前所未有的结构细节.
- 这些发现揭示了BAF重塑染色体的机制,并突出了SMARCB1等子单元中癌症相关突变的结构意义.
- 确定的结构是了解BAF在基因调节中的功能及其在瘤发生中的作用的基础.
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