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| Subject Categories: Membranes & Transport | Differentiation & Death |
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| The EMBO Journal
(2006) 25, 2287–2296, doi:10.1038/sj.emboj.7601126 Published online 27 April 2006 |
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| Bcl-2 changes conformation to inhibit Bax oligomerization |
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| Paulina J Dlugosz1, Lieven P Billen1, Matthew G Annis1, Weijia Zhu1, Zhi Zhang3, Jialing Lin3, Brian Leber1, 2 and David W Andrews1 |
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1 Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, CDN-Hamilton, Ontario, Canada 2 Department of Medicine, McMaster University Health Sciences Centre, CDN-Hamilton, Ontario, Canada 3 Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA To whom correspondence should be addressed David W Andrews, Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, 4H41B-1200 Main Street West, CDN-Hamilton, Ontario, Canada L8N 3Z5. Tel.: +1 905 525 9140 ext 22075; Fax: +1 905 522 9033; E-mail: andrewsd@mcmaster.ca Received 3 November 2005; Accepted 11 April 2006; Published online 27 April 2006. |
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| Abstract |
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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  5–6 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. |
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| Keywords: apoptosis, Bax, Bcl-2, membrane topology, tBid |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHBax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis The EMBO Journal Article (15 Jun 2005) Cell Death and Differentiation Original Article |
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