Cowan Angus D, Smith Nicholas A, Sandow Jarrod J, Kapp Eugene A, Rustam Yepy H, Murphy James M, Brouwer Jason M, Bernardini Jonathan P, Roy Michael J, Wardak Ahmad Z, Tan Iris K, Webb Andrew I, Gulbis Jacqueline M, Smith Brian J, Reid Gavin E, Dewson Grant, Colman Peter M, Czabotar Peter E
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Nat Struct Mol Biol. 2020 Nov;27(11):1024-1031. doi: 10.1038/s41594-020-0494-5. Epub 2020 Sep 14.
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.
BAK和BAX是细胞凋亡的重要介质，它们响应死亡信号而发生寡聚化，从而导致线粒体外膜通透性增加。它们从静止单体转变为形成孔道的寡聚体涉及一个特征明确的对称二聚体中间体。然而，尚未鉴定出可通过诱变破坏的关键二级界面。在此，我们描述了人BAK核心结构域（α2-α5）二聚体的晶体结构，该结构揭示了膜脂和去污剂的优先结合位点。磷脂头部基团和一条酰基链（sn2）与一个核心二聚体结合，而另一条酰基链（sn1）与相邻的核心二聚体结合，这表明了脂质促进BAK寡聚化的机制。我们的数据支持这样一种模型，即与其他主要通过蛋白质-蛋白质界面将单体组装成寡聚体的成孔蛋白不同，膜本身在BAK和BAX寡聚化过程中发挥作用。
