Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Nat Struct Mol Biol. 2013 May;20(5):589-97. doi: 10.1038/nsmb.2563. Epub 2013 Apr 21.
The BCL-2-family protein BAK is responsible for mitochondrial outer-membrane permeabilization (MOMP), which leads to apoptosis. The BCL-2 homology 3 (BH3)-only protein BID activates BAK to perform this function. We report the NMR solution structure of the human BID BH3-BAK complex, which identified the activation site at the canonical BH3-binding groove of BAK. Mutating the BAK BH1 in the groove prevented activation and MOMP but not the binding of BID. BAK BH3 mutations allowed BID binding and activation but blunted function by blocking BAK oligomerization. BAK activation follows a 'hit-and-run' mechanism whereby BID dissociates from the trigger site, which allows BAK oligomerization at an overlapping interface. In contrast, the BH3-only proteins NOXA and BAD are predicted to clash with the trigger site and are not activators of BAK. These findings provide insights into the early stages of BAK activation.
BCL-2 家族蛋白 BAK 负责线粒体外膜通透性（MOMP），从而导致细胞凋亡。BCL-2 同源结构域 3（BH3）仅存在于蛋白 BID 激活 BAK 来执行此功能。我们报告了人类 BID BH3-BAK 复合物的 NMR 溶液结构，该结构确定了 BAK 经典 BH3 结合槽中的激活位点。在槽中突变 BAK BH1 可防止激活和 MOMP，但不阻止 BID 的结合。BAK BH3 突变允许 BID 结合和激活，但通过阻止 BAK 寡聚化而削弱功能。BAK 的激活遵循“打了就跑”的机制，即 BID 从触发位点解离，从而允许 BAK 在重叠的界面上寡聚化。相比之下，BH3 仅存在于蛋白 NOXA 和 BAD 预计会与触发位点发生冲突，并且不是 BAK 的激活剂。这些发现为 BAK 激活的早期阶段提供了深入的了解。
