Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane
- Westphal, D; Dewson, G; Menard, M; Frederick, P; Iyer, S; Bartolo, R; Gibson, L; Czabotar, PE; Smith, BJ; Adams, JM; Kluck, RM;
Publication Year 2014-09-16, Volume 111, Issue #39, Page E4706-E4085
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type
- Journal Article
- The pivotal step on the mitochondrial pathway to apoptosis is permeabilization of the mitochondrial outer membrane (MOM) by oligomers of the B-cell lymphoma-2 (Bcl-2) family members Bak or Bax. However, how they disrupt MOM integrity is unknown. A longstanding model is that activated Bak and Bax insert two alpha-helices, alpha5 and alpha6, as a hairpin across the MOM, but recent insights on the oligomer structures question this model. We have clarified how these helices contribute to MOM perforation by determining that, in the oligomers, Bak alpha5 (like Bax alpha5) remains part of the protein core and that a membrane-impermeable cysteine reagent can label cysteines placed at many positions in alpha5 and alpha6 of both Bak and Bax. The results are inconsistent with the hairpin insertion model but support an in-plane model in which alpha5 and alpha6 collapse onto the membrane and insert shallowly to drive formation of proteolipidic pores.
- National Academy of Sciences
- WEHI Research Division(s)
- Molecular Genetics Of Cancer; Cell Signalling And Cell Death; Structural Biology
- Publisher's Version
- Open Access at Publisher's Site
- Rights Notice
- Freely available online through the PNAS open access option.
Creation Date: 2014-09-19 09:42:38Last Modified: 0001-01-01 12:00:00