Figure 3

Model for life/death decisions on the MOM, showing how pro-survival family members constrain BAX (and BAK) and how BH3-only proteins (here BIM) drive their activation. In healthy cells, monomeric BAX shuttles between the cytosol and MOM, where VDAC2 acts as a receptor (also for BAK), although pro-survival relatives (here BCL-X_L) can ‘retro-translocate’ MOM-bound BAX back to the cytosol.³⁶ Upon apoptotic signalling, to allow more BAX to move to the MOM (step 1), where most BAK molecules reside, an activator BH3-only protein such as BIM may transiently engage a BAX ‘rear site’ involving helices α1 and α6,^{130, 131} thereby releasing the C-terminal trans-membrane (TM) domain (α9) from its surface groove to enable MOM binding. Then, groove binding by the activator drives release of the N terminus and α1 of BAX or BAK (pale orange) (step 2) and all subsequent activation steps for both the MOM-bound effector proteins. The most dramatic change is the unfolding of BAX and BAK that separates their ‘latch’ domain (α6–α8; speckled orange) from their ‘core’ domain (α2–α5)^{41, 43} (step 3); this ejects the BH3-only activator (BIM here) and exposes the BH3 domain of BAX or BAK (α2, red triangle) (step 4). If pro-survival proteins are available to bind the exposed BAX (or BAK) BH3 domain, apoptosis aborts (step 5a). However, if pro-survival proteins are largely occupied by BH3-only proteins, the unfolded BAK or BAX monomers form homodimers through reciprocal BH3/groove interactions of their core domains (step 5b).^{41, 43, 46, 47} The core dimers are the central unit of the BAX and BAK homo-oligomers,^{46, 47, 132} but how they associate into oligomers (step 6) remains uncertain, as does how the oligomers drive MOM permeabilisation (see text). Modified, with permission, from Figure 3 of Cory et al.⁸