Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
Cell Rep. 2020 Mar 10;30(10):3229-3239.e6. doi: 10.1016/j.celrep.2020.02.057.
BCL-2 family proteins converge at the mitochondrial outer membrane to regulate apoptosis and maintain the critical balance between cellular life and death. This physiologic process is essential to organism homeostasis and relies on protein-protein and protein-lipid interactions among BCL-2 family proteins in the mitochondrial lipid environment. Here, we find that trans-2-hexadecenal (t-2-hex), previously implicated in regulating BAX-mediated apoptosis, does so by direct covalent reaction with C126, which is located on the surface of BAX at the junction of its α5/α6 core hydrophobic hairpin. The application of nuclear magnetic resonance spectroscopy, hydrogen-deuterium exchange mass spectrometry, specialized t-2-hex-containing liposomes, and BAX mutational studies in mitochondria and cells reveals structure-function insights into the mechanism by which covalent lipidation at the mitochondria sensitizes direct BAX activation. The functional role of BAX lipidation as a control point of mitochondrial apoptosis could provide a therapeutic strategy for BAX modulation by chemical modification of C126.
BCL-2 家族蛋白在线粒体膜上汇聚，调节细胞凋亡，维持细胞生死的关键平衡。这一生理过程对于生物体内稳态至关重要，依赖于线粒体脂环境中 BCL-2 家族蛋白之间的蛋白-蛋白和蛋白-脂相互作用。在这里，我们发现先前涉及调节 BAX 介导的细胞凋亡的反式-2-十六烯醛（t-2-hex）通过与位于 BAX 的 α5/α6 核心疏水性发夹连接处表面的 C126 的直接共价反应来实现这一点。核磁共振波谱、氢氘交换质谱、含有特殊 t-2-hex 的脂质体以及在线粒体和细胞中进行的 BAX 突变研究揭示了共价脂化如何在敏感直接激活 BAX 方面的结构-功能机制。BAX 脂化作为线粒体凋亡的控制点的功能作用可以通过化学修饰 C126 来提供 BAX 调节的治疗策略。
