Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane.

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.

authors

Westphal D,Dewson G,Menard M,Frederick P,Iyer S,Bartolo R,Gibson L,Czabotar PE,Smith BJ,Adams JM,Kluck RM

doi

10.1073/pnas.1415142111

subject

Has Abstract

pub_date

2014-09-30 00:00:00

pages

E4076-85

issue

39

eissn

0027-8424

issn

1091-6490

pii

1415142111

journal_volume

111

pub_type

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