Inhibition of Oligomeric BAX by an Anti-Apoptotic Dimer

BAX is a pro-apoptotic BCL-2 protein that resides in the cytosol as a monomer until triggered by cellular stress to transform into an oligomer that permeabilizes the mitochondria and induces apoptosis. We previously reported the generation of a full-length BAX oligomer (BAXO) that recapitulates pro-apoptotic functionality. Here, we find that full-length BCL-w can be induced to form a symmetric dimer (BCL-wD) that dissociates BAXO, inhibits its mitochondrial translocation, induces its retrotranslocation, and thereby blocks its membrane-porating activity. Structure-function analyses revealed discrete conformational changes upon BCL-w dimerization and reciprocal structural impacts upon BCL-wD and BAXO interaction. SAXS analysis demonstrated that BAXO forms pores by inducing negative Gaussian membrane curvature, which is reversed by positive Gaussian curvature exerted by BCL-wD. Our studies reveal an additional mechanism of apoptotic regulation mediated by the protein and membrane interactions of higher-order BCL-2 family multimers, redefining the “point of no return” for BAX-mediated apoptosis.