Kao Te-Yu, Tsai Chia-Jung, Lan Yu-Jing, Chiang Yun-Wei
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
Phys Chem Chem Phys. 2017 Apr 5;19(14):9584-9591. doi: 10.1039/c7cp00401j.
While activation of BAX is required for initiating mitochondria-mediated apoptosis, the underlying mechanisms remain unsettled. We studied conformations of BAX protein using pressure- and temperature-resolved ESR techniques and obtained the thermodynamic properties of the conformations. We show that inactive BAX is structurally heterogeneous and exists in equilibrium between two major populations of the conformations, UM and UM', of which the former is thermodynamically favored at room temperature. An increase in the population of UM', induced by either pressure or point mutations of BAX, renders BAX susceptible to oligomerization, which leads to cell death. This study uncovers the biological significance of BAX conformations and shows that the pro-apoptotic activity of BAX can be triggered by altering the equilibrium between the two states. It suggests that therapeutic intervention may focus on shifting the balance in the conformational heterogeneity.
虽然启动线粒体介导的细胞凋亡需要BAX激活，但其潜在机制仍未明确。我们使用压力和温度分辨电子顺磁共振技术研究了BAX蛋白的构象，并获得了这些构象的热力学性质。我们发现，无活性的BAX在结构上是异质的，存在于两种主要构象群体UM和UM'之间的平衡中，其中前者在室温下在热力学上更有利。由压力或BAX的点突变诱导的UM'群体增加，使BAX易于寡聚化，从而导致细胞死亡。这项研究揭示了BAX构象的生物学意义，并表明可以通过改变两种状态之间的平衡来触发BAX的促凋亡活性。这表明治疗干预可能集中在改变构象异质性中的平衡。
