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 ?-helices, ?5 and ?6, 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 ?5 (like Bax ?5) remains part of the protein core and that a membrane-impermeable cysteine reagent can label cysteines placed at many positions in ?5 and ?6 of both Bak and Bax. The results are inconsistent with the hairpin insertion model but support an in-plane model in which ?5 and ?6 collapse onto the membrane and insert shallowly to drive formation of proteolipidic pores.

SUBMITTER: Westphal D 

PROVIDER: S-EPMC4191798 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature