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内源性人类BAF复合物结构模型破译疾病机制
作者:小柯机器人 发布时间:2020/10/15 15:33:45

美国丹娜-法伯癌症研究所Cigall Kadoch等研究人员合作通过内源性人类BAF复合物的结构模型破译疾病机制。相关论文于2020年10月13日在线发表于国际学术期刊《细胞》。

研究人员报道了使用冷冻电镜(cryo-EM)、交联质谱和同源性建模生成的内源性人类经典BAF复合物与核小体结合的结构模型。BAF复合物通过SMARCB1 C末端α-螺旋和SMARCA4/2 C末端SnAc/SnAc后区域双边接合核小体H2A/H2B酸性斑块区域,而与疾病相关的突变均导致染色质重塑活性减弱。此外,研究人员定义了核小体结合后BAF复合物结构的变化,并将内源性BAF的结构模型与相关的SWI/SNF家族复合物的结构模型进行了比较。

最后,研究人员区分并实验性地研究了内源性人类BAF复合物中的与癌症相关的热点突变,确定了那些破坏核小体结合构象中的BAF亚基-亚基和亚基-核小体界面的突变。总之,这种整合型结构方法为理解BAF在正常和疾病状态下复杂功能的机制提供了重要的生物物理基础。

据介绍,哺乳动物SWI/SNF复合物是调节基因组结构的ATP依赖性染色质重塑复合物。

附:英文原文

Title: A Structural Model of the Endogenous Human BAF Complex Informs Disease Mechanisms

Author: Nazar Mashtalir, Hiroshi Suzuki, Daniel P. Farrell, Akshay Sankar, Jie Luo, Martin Filipovski, Andrew R. D’Avino, Roodolph St. Pierre, Alfredo M. Valencia, Takashi Onikubo, Robert G. Roeder, Yan Han, Yuan He, Jeffrey A. Ranish, Frank DiMaio, Thomas Walz, Cigall Kadoch

Issue&Volume: 2020-10-13

Abstract: Mammalian SWI/SNF complexes are ATP-dependent chromatin remodeling complexes thatregulate genomic architecture. Here, we present a structural model of the endogenouslypurified human canonical BAF complex bound to the nucleosome, generated using cryoelectronmicroscopy (cryo-EM), cross-linking mass spectrometry, and homology modeling. BAFcomplexes bilaterally engage the nucleosome H2A/H2B acidic patch regions through theSMARCB1 C-terminal α-helix and the SMARCA4/2 C-terminal SnAc/post-SnAc regions, withdisease-associated mutations in either causing attenuated chromatin remodeling activities.Further, we define changes in BAF complex architecture upon nucleosome engagementand compare the structural model of endogenous BAF to those of related SWI/SNF-familycomplexes. Finally, we assign and experimentally interrogate cancer-associated hot-spotmutations localizing within the endogenous human BAF complex, identifying those thatdisrupt BAF subunit-subunit and subunit-nucleosome interfaces in the nucleosome-boundconformation. Taken together, this integrative structural approach provides importantbiophysical foundations for understanding the mechanisms of BAF complex function innormal and disease states.

DOI: 10.1016/j.cell.2020.09.051

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31248-4

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/