Key result
Altering BAX conformation equilibrium via pressure or point mutations triggers pro-apoptotic activity and cell death.
Why the study?
The mechanisms underlying BAX activation in mitochondria-mediated apoptosis remain unsettled, particularly the role of its conformational heterogeneity.
The pro-apoptotic activity of BAX can be triggered by altering the equilibrium between its two conformational states, suggesting a potential therapeutic target.
Animal data identify BAX conformational equilibrium as a potential apoptosis switch; leaves open therapeutic targeting in human disease.
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.
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Kao et al. (2017) studied Apoptosis. Pressure or point mutations was evaluated on BAX oligomerization and cell death. Altering the equilibrium between the UM and UM' conformations of BAX via pressure or point mutations triggers its pro-apoptotic activity and leads to cell death.
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