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 alpha5-alpha6 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.
Mesh Terms:
Animals, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Cell Line, Cell Membrane, Cytochromes c, Humans, Mitochondria, Models, Molecular, Mutagenesis, Site-Directed, Protein Conformation, Proto-Oncogene Proteins c-bcl-2, Rats, bcl-2-Associated X Protein
Animals, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Cell Line, Cell Membrane, Cytochromes c, Humans, Mitochondria, Models, Molecular, Mutagenesis, Site-Directed, Protein Conformation, Proto-Oncogene Proteins c-bcl-2, Rats, bcl-2-Associated X Protein
EMBO J.
Date: Jun. 07, 2006
PubMed ID: 16642033
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