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  • The EMBO Journal (2006) 25, 2287 - 2296
  • doi:10.1038/sj.emboj.7601126

Published online: 27 April 2006

Bcl-2 changes conformation to inhibit Bax oligomerization

Paulina J Dlugosz1, Lieven P Billen1, Matthew G Annis1, Weijia Zhu1, Zhi Zhang3, Jialing Lin3, Brian Leber1,2 and David W Andrews1

  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

Correspondence to:

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

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.

  • Keywords:

    • apoptosis,
    • Bax,
    • Bcl-2,
    • membrane topology,
    • tBid