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.
BCL-2 proteins regulate mitochondrial outer membrane permeabilization (MOMP). BCL-xL shuttles between cytoplasm and outer mitochondrial membrane (OMM) to block BID, PUMA and p53. BID, a canonical direct effector activator, triggers BAK and BAX to dimerize and oligomerize into pores that mediate MOMP. Upon displacement from BCL-xL by PUMA, p53 triggers BAX noncanonically. Structural analysis of membrane associated intermediates is lacking.