Abstract:
: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 α-helices, α5 and α6, 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 α5 (like Bax α5) remains part of the protein core and that a membrane-impermeable cysteine reagent can label cysteines placed at many positions in α5 and α6 of both Bak and Bax. The results are inconsistent with the hairpin insertion model but support an in-plane model in which α5 and α6 collapse onto the membrane and insert shallowly to drive formation of proteolipidic pores.
journal_name
Proc Natl Acad Sci U S Aauthors
Westphal D,Dewson G,Menard M,Frederick P,Iyer S,Bartolo R,Gibson L,Czabotar PE,Smith BJ,Adams JM,Kluck RMdoi
10.1073/pnas.1415142111subject
Has Abstractpub_date
2014-09-30 00:00:00pages
E4076-85issue
39eissn
0027-8424issn
1091-6490pii
1415142111journal_volume
111pub_type
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