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BAK core dimers bind lipids and can be bridged by them.
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2020-09-14 , DOI: 10.1038/s41594-020-0494-5
Angus D Cowan 1, 2 , Nicholas A Smith 3 , Jarrod J Sandow 1, 2 , Eugene A Kapp 4, 5, 6 , Yepy H Rustam 4, 5, 6 , James M Murphy 1, 2 , Jason M Brouwer 1, 2 , Jonathan P Bernardini 1, 2 , Michael J Roy 1, 2 , Ahmad Z Wardak 1 , Iris K Tan 1 , Andrew I Webb 1, 2 , Jacqueline M Gulbis 1, 2 , Brian J Smith 3 , Gavin E Reid 4, 5, 6 , Grant Dewson 1, 2 , Peter M Colman 1, 2 , Peter E Czabotar 1, 2
Affiliation  

BAK and BAX are essential mediators of apoptosis that oligomerize in response to death cues, thereby causing permeabilization of the mitochondrial outer membrane. Their transition from quiescent monomers to pore-forming oligomers involves a well-characterized symmetric dimer intermediate. However, no essential secondary interface that can be disrupted by mutagenesis has been identified. Here we describe crystal structures of human BAK core domain (α2–α5) dimers that reveal preferred binding sites for membrane lipids and detergents. The phospholipid headgroup and one acyl chain (sn2) associate with one core dimer while the other acyl chain (sn1) associates with a neighboring core dimer, suggesting a mechanism by which lipids contribute to the oligomerization of BAK. Our data support a model in which, unlike for other pore-forming proteins whose monomers assemble into oligomers primarily through protein–protein interfaces, the membrane itself plays a role in BAK and BAX oligomerization.



中文翻译:

BAK 核心二聚体结合脂质并可被它们桥接。

BAK 和 BAX 是细胞凋亡的重要介质,它们响应死亡信号而寡聚化,从而导致线粒体外膜的透化。它们从静止单体到成孔低聚物的转变涉及一个充分表征的对称二聚体中间体。然而,没有发现可以被诱变破坏的基本二级界面。在这里,我们描述了人类 BAK 核心域(α2-α5)二聚体的晶体结构,这些结构揭示了膜脂和去污剂的首选结合位点。磷脂头部基团和一个酰基链(SN 2)相关联的一个核心二聚体,而另一个酰基链(SN1) 与相邻的核心二聚体相关联,表明脂质有助于 BAK 寡聚化的机制。我们的数据支持一个模型,其中与其他成孔蛋白的单体主要通过蛋白质 - 蛋白质界面组装成寡聚体不同,膜本身在 BAK 和 BAX 寡聚化中起作用。

更新日期:2020-09-14
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