title: Bcl-2 changes conformation to inhibit Bax oligomerization.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, CDN-Hamilton, Ontario, Canada.
authors.forename: Paulina J
authors.initials: PJ
authors.lastname: Dlugosz
authors.forename: Lieven P
authors.initials: LP
authors.lastname: Billen
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Annis
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jialing
authors.initials: J
authors.lastname: Lin
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000648:ultrastructure; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051028:bcl-2-Associated X Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c