Bcl‐2 changes conformation to inhibit Bax oligomerization

Bcl‐2 inhibits apoptosis by regulating the release of cytochrome c and other proteins from mitochondria. Oligomerization of Bax promotes cell death by permeabilizing the outer mitochondrial membrane. In transfected cells and isolated mitochondria, Bcl‐2, but not the inactive point mutants Bcl‐2‐G145A and Bcl‐2‐V159D, undergoes a conformation change in the mitochondrial membrane in response to apoptotic agonists such as tBid and Bax. A mutant Bcl‐2 with two cysteines introduced at positions predicted to result in a disulfide bond that would inhibit the mobility of α5–α6 helices (Bcl‐2‐S105C/E152C) was only active in a reducing environment. Thus, Bcl‐2 must change the conformation to inhibit tBid‐induced oligomerization of integral membrane Bax monomers and small oligomers. The conformationally changed Bcl‐2 sequesters the integral membrane form of Bax. If Bax is in excess, apoptosis resumes as Bcl‐2 is consumed by the conformational change and in complexes with Bax. Thus, Bcl‐2 functions as an inhibitor of mitochondrial permeabilization by changing conformation in the mitochondrial membrane to bind membrane‐inserted Bax monomers and prevent productive oligomerization of Bax.