Many players in BCL-2 family affairs

•Binding-induced conformational transitions within BCL-2 family proteins regulate apoptosis.•Canonical and non-canonical ligand binding occurs at the globular BCL-2 cores.•Allosteric activation of BCL-2 effectors initiates mitochondrial outer-membrane permeabilization (MOMP).•PUMA-induced unfolding of BCL-xL releases p53 to trigger BCL-2 effectors and MOMP.

During apoptotic cell death, cellular stress signals converge at the mitochondria to induce mitochondrial outer-membrane permeabilization (MOMP) through B cell lymphoma-2 (BCL-2) family proteins and their effectors. BCL-2 proteins function through protein–protein interactions, the mechanisms and structural aspects of which are only now being uncovered. Recently, the elucidation of the dynamic features underlying their function has highlighted their structural plasticity and the consequent complex thermodynamic landscape governing their protein–protein interactions. These studies show that canonical interactions involve a conserved, hydrophobic groove, whereas non-canonical interactions function allosterically outside the groove. We review the latest structural advances in understanding the interactions and functions of mammalian BCL-2 family members, and discuss new opportunities to modulate these proteins in health and disease.