Table 1. Comparison of the three models of BH3-only-mediated Bax/Bak activation.

Model of Bax/Bak Activation	Targets of the BH3-only proteins	BH3-only– Bax/Bak Interaction	Activation Mechanism	Direct Activator	Trigger Site on Bax/Bak	Driving Force
Indirect Activation (Displacement)	Anti-apoptotic Bcl- 2 proteins	None	Displacement and De- repression	None	None	Stable BH3- only–Bcl-xL/Mcl-1 interaction
Direct Activation	Bax/Bak and anti- apoptotic Bcl-2 proteins	Yes	De novo and direct activation	Activator BH3- only proteins	Helices 1/6 or the hydrophobic groove	Transient BH3 (BH3-only)–groove (Bax/Bak) interaction
Membrane (lipids)-mediated Spontaneous Activation	Anti-apoptotic Bcl- 2 proteins	None	De novo and direct activation	Mitochondrial outer membrane (lipids)	C-terminal tail (helix 9)	Stable BH3- only–Bcl-xL/Mcl-1 interaction, free diffusion, and stable Bax/Bak α9-membrane interaction