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.
Dlugosz
Paulina J
PJ
Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, CDN-Hamilton, Ontario, Canada.
Billen
Lieven P
LP
Annis
Matthew G
MG
Zhu
Weijia
W
Zhang
Zhi
Z
Lin
Jialing
J
Leber
Brian
B
Andrews
David W
DW
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*
D051023:BH3 Interacting Domain Death Agonist Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c