Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Nat Commun. 2022 Jan 11;13(1):250. doi: 10.1038/s41467-021-27851-y.
BCL-2 proteins regulate mitochondrial poration in apoptosis initiation. How the pore-forming BCL-2 Effector BAK is activated remains incompletely understood mechanistically. Here we investigate autoactivation and direct activation by BH3-only proteins, which cooperate to lower BAK threshold in membrane poration and apoptosis initiation. We define in trans BAK autoactivation as the asymmetric "BH3-in-groove" triggering of dormant BAK by active BAK. BAK autoactivation is mechanistically similar to direct activation. The structure of autoactivated BAK BH3-BAK complex reveals the conformational changes leading to helix α1 destabilization, which is a hallmark of BAK activation. Helix α1 is destabilized and restabilized in structures of BAK engaged by rationally designed, high-affinity activating and inactivating BID-like BH3 ligands, respectively. Altogether our data support the long-standing hit-and-run mechanism of BAK activation by transient binding of BH3-only proteins, demonstrating that BH3-induced structural changes are more important in BAK activation than BH3 ligand affinity.
BCL-2 蛋白调节凋亡起始中的线粒体穿孔。BH3 仅蛋白如何激活形成孔道的 BCL-2 效应因子 BAK 在机制上仍不完全清楚。在这里，我们研究了自激活和 BH3 仅蛋白的直接激活，它们共同降低了膜穿孔和凋亡起始中 BAK 的阈值。我们将跨向 BAK 自激活定义为活性 BAK 对休眠 BAK 的不对称“BH3 在凹槽中”触发。BAK 自激活在机制上类似于直接激活。自激活 BAK BH3-BAK 复合物的结构揭示了导致螺旋 α1 失稳的构象变化，这是 BAK 激活的标志。在通过合理设计的高亲和力激活和失活 BID 样 BH3 配体分别与 BAK 结合的结构中，螺旋 α1 失稳并重新稳定。总的来说，我们的数据支持 BAK 通过 BH3 仅蛋白的短暂结合进行的 hit-and-run 激活的长期存在的机制，表明 BH3 诱导的结构变化在 BAK 激活中比 BH3 配体亲和力更为重要。
