Discoveries and controversies in BCL 2 protein mediated apoptosis
B cell lymphoma 2 (BCL 2) family proteins mediate mitochondrial apoptosis by regulating mitochondrial outer membrane permeabilization (MOMP) which leads to the activation of the downstream caspase cascade to execute apoptosis. The pro apoptotic and anti apoptotic BCL 2 proteins function through protein protein interactions in soluble and membrane associated states. How soluble BCL 2 proteins interact is well understood. Anti apoptotic proteins, such as BCL 2 and BCL xL, and the pro apoptotic effectors of MOMP, including BAK and BAX, interact with pro apoptotic BCL 2 homology 3 (BH3) only proteins similarly. Whereas anti apoptotic BCL 2 proteins tightly bind all the BH3 only proteins to block apoptosis initiation, the effector BCL 2 proteins are potently triggered by specific BH3 only proteins to undergo conformational changes, membrane association and insertion, oligomerization, and pore formation. The anti apoptotic BCL 2 proteins also inhibit the activated effectors. p53 is a direct BAX activator inhibited by BCL xL, defining a prototype non canonical modulator of BCL 2 proteins mediated MOMP. How BCL 2 proteins cooperate in the presence of membranes remains poorly understood, impeding our understanding of MOMP and apoptosis. Here, we highlight the latest structural views of MOMP by BCL 2 proteins.
The FEBS journal