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Structure of a meiosis-specific complex central to BRCA2 localization at recombination sites
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2021-08-09 , DOI: 10.1038/s41594-021-00635-0
Devon F Pendlebury 1, 2, 3 , Jingjing Zhang 4 , Ritvija Agrawal 1 , Hiroki Shibuya 4 , Jayakrishnan Nandakumar 1, 2
Affiliation  

Meiotic cells invoke breast cancer susceptibility gene 2 (BRCA2) to repair programmed double-stranded DNA breaks and accomplish homologous recombination. The meiosis-specific protein MEILB2 facilitates BRCA2 recruitment to meiotic recombination sites. Here, we combine crystallography, biochemical analysis and a mouse meiosis model to reveal a robust architecture that ensures meiotic BRCA2 recruitment. The crystal structure of the MEILB2–BRCA2 complex reveals how two MEILB2 homodimers sandwich two chains of BRCA2 to afford a 4:2 architecture. The sandwich lacks close contact between the two MEILB2 dimers or the two BRCA2 chains. Instead, the two halves of each BRCA2 chain bridge two MEILB2 subunits from different homodimers to form the MEILB2–BRCA2–MEILB2 sandwich. Several identical residues from the two MEILB2 subunits are employed to engage the BRCA2 halves, justifying their strict conservation. Mutational analysis of the interface reveals a synergistic mechanism for MEILB2–BRCA2 recruitment during meiosis. Overall, these studies demonstrate how BRCA2 efficiently localizes in the cell to facilitate meiosis.



中文翻译:

重组位点 BRCA2 定位中心的减数分裂特异性复合物的结构

减数分裂细胞调用乳腺癌易感基因 2 ( BRCA2) 修复程序化的双链 DNA 断裂并完成同源重组。减数分裂特异性蛋白 MEILB2 促进 BRCA2 募集到减数分裂重组位点。在这里,我们将晶体学、生化分析和小鼠减数分裂模型结合起来,揭示了一种确保减数分裂 BRCA2 募集的稳健架构。MEILB2-BRCA2 复合物的晶体结构揭示了两个 MEILB2 同源二聚体如何将两条 BRCA2 链夹在中间以提供 4:2 结构。三明治缺乏两个 MEILB2 二聚体或两个 BRCA2 链之间的紧密接触。相反,每个 BRCA2 链的两半桥接来自不同同源二聚体的两个 MEILB2 亚基,形成 MEILB2-BRCA2-MEILB2 三明治。来自两个 MEILB2 亚基的几个相同的残基被用来接合 BRCA2 的一半,证明它们的严格保护是合理的。界面的突变分析揭示了减数分裂过程中 MEILB2-BRCA2 募集的协同机制。总的来说,这些研究证明了 BRCA2 如何有效地定位在细胞中以促进减数分裂。

更新日期:2021-08-09
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