Lipids modulate the BH3-independent membrane targeting and activation of BAX and Bcl-xL
Victor Vasquez‐Montes, Mykola V. Rodnin, Alexander Kyrychenko, Alexey S. Ladokhin
Abstract
Significance Here, we characterize a mechanism that modulates the membrane targeting, refolding, and activation of the apoptotic regulators BAX and Bcl-xL in the absence of their canonical activators (BH3-only effector proteins). The critical component of the suggested mechanism is the enrichment of the mitochondrial outer membrane with anionic lipids, primarily cardiolipin. This lipid-dependent activation is found to be coupled to the presence of physiologically relevant concentrations of divalent cations. Membrane insertion of Bcl-xL results in the release of the BH4 regulatory domain from the folded structure, leading to inhibition of pore formation by BAX. These results provide a mechanistic rationale for recent cellular studies that demonstrate the mitochondrial localization and activity of BAX and Bcl-xL in cells lacking BH3-only effectors.