Two models for how BH3-only proteins activate Bax and Bak. (A) In the direct activation model [], the indicated activator BH3-only proteins, via their BH3 domain (red triangle), directly engage Bax and Bak and activate them, whereas sensitizer BH3-only proteins (e.g. Bad or Noxa), which can only bind the pro-survival proteins, serve only to displace activators from the pro-survival proteins. (B) In the indirect activation model [,,] the BH3-only proteins only bind the pro-survival proteins. Because the promiscuous binders (Bim, tBid, Puma) can neutralise all pro-survival proteins, each can readily trigger Bax/Bak activation, whereas any selective binder (eg. Bad) must be co-expressed with a complementary binder (e.g. Noxa) to do so.

Model for constraint of Bak (top) and Bax (bottom) by pro-survival family members [,,]. (A) In unperturbed cells or early in apoptotic signalling, a small proportion of Bak and Bax molecules is proposed to acquire a ‘primed’ conformation in which their BH3 domains are accessible but engaged by the indicated pro-survival proteins (and perhaps also A1). The priming might require an independent undetermined signal, particularly to recruit Bax from the cytosol. (B) In apoptotic cells, once BH3-only proteins (‘BH3’), or a BH3 mimic, have engaged the appropriate pro-survival proteins, the freed primed Bak or Bax can nucleate the oligomerization thought to permeabilize the outer mitochondrial membrane and thereby commit the cell to apoptosis. The pro-survival proteins also appear to have a mode of constraint that does not rely upon association via the Bax/Bak BH3 domain (see text).

Models for resistance/sensitivity of tumor cells to a selective BH3 mimetic like ABT-737 (red arrowhead) that binds tightly to Bcl-x_L, Bcl-2 and Bcl-w but not to Mcl-1 or A1. (A) High Mcl-1 (dark blue) renders the cell refractory, because Mcl-1 can capture the Bak released from Bcl-x_L by the drug. (B) In cells with little Mcl-1 (light blue) (or A1), the freed Bak can initiate apoptosis. (C) The high Bcl-2 (or Bcl-x_L) found in many tumors can sequester a high level of Bim [] and prevent Bim from inducing apoptosis. Paradoxically, this can actually enhance sensitivity to ABT-737, because the Bim released by ABT-737 from Bcl-2 (or Bcl-x_L) can inactivate the ABT-737-insensitive Mcl-1 (or A1), freeing Bak to drive apoptosis.

Potential coupling of apoptosis and autophagy via Beclin 1 and Bcl-2 homologs. The model assumes that, in a favourable environment, pro-survival proteins such as Bcl-2 and Bcl-x_L prevent Beclin 1 from inducing autophagy by sequestering it, seemingly on the ER [,]. If so, the engagement of the pro-survival proteins by BH3-only proteins (or BH3 mimics) should trigger autophagy as well as apoptosis. In settings such as nutrient limitation or cytokine deprivation, autophagy temporarily prolongs survival by ensuring adequate ATP levels [,], but in response to cytotoxic drugs, including some used in chemotherapy, it appears instead to promote autophagic cell death []. How this dichotomy is controlled is not known.