Cytosolic BAX Can Form Autoinhibited Dimers to Suppress Apoptosis

The proapoptotic BAX protein triggers apoptosis via the intrinsic pathway by inducing mitochondrial outer membrane permeabilization (MOMP). BAX largely exists in an inactive conformation in the cytoplasm, but under cellular stress BAX is activated by BH3-only proteins and translocates to the mitochondrial outer membrane to induce MOMP. Structural studies have revealed conformational changes at the N-terminal surface and C-terminal α9 helix that are required for BAX activation by BH3 proteins and MOMP induction, but suggest that additional mechanisms may stabilize BAX in the inactive cytosolic conformation. Garner, Reyna, and colleagues identified an autoinhibited dimeric BAX conformation in addition to the inactive monomer conformation. The BAX dimers did not induce membrane permeabilization, and, in contrast to BAX monomers, were resistant to BH3-mediated activation. Moreover, BAX dimers failed to translocate to the membrane upon BH3-induced stimulation. Crystallization studies indicated that the BAX dimer exhibited an asymmetric conformation; the N-terminal BAX activation site of one BAX monomer interacted with the C-terminal surface (including C-terminal helix α9) of the other BAX monomer. BAX monomers are activated by BH3 binding to the N-terminal activation site, triggering a conformational change, but in the BAX dimer, helix α9 from one monomer bound to the N-terminal activation site of the other, maintaining a closed and inactive conformation refractory to BH3 activation. Dissociation of the BAX dimer into monomers was required for BH3 binding and BAX activation. In mouse embryonic fibroblasts, wild-type BAX dimers reduced apoptosis, whereas dimerization-impaired BAX exhibited increased apoptosis, pointing to a role for inactive BAX dimers in regulation of BAX-dependent apoptosis. The identification of cytosolic autoinhibited BAX dimers reveals an additional mechanism by which BAX activation and apoptosis can be regulated, and may be useful in developing pharmacologic BAX modulators.

Garner TP, Reyna DE, Priyadarshi A, Chen HC, Li S, Wu Y, et al. An autoinhibited dimeric form of BAX regulates the BAX activation pathway. Mol Cell 2016;63:485–97.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.