title: Mechanistic differences in the membrane activity of Bax and Bcl-xL correlate with their opposing roles in apoptosis.
abstract: Based on their membrane-permeabilizing activity in vitro, it has been proposed that Bax-like proteins induce cytochrome c release during apoptosis via pore formation. However, antiapoptotic Bcl-2 proteins, which inhibit cytochrome c release, also display pore activity in model membranes. As a consequence, a unified description that aligns the pore activity of the Bcl-2 proteins with their apoptotic function is missing. Here, we studied the mechanism of membrane binding, oligomerization, and permeabilization by pro- and antiapoptotic Bcl-2 members at the single-vesicle level. We found that proapoptotic Bax forms large, stable pores via an all-or-none mechanism that can release cytochrome c. In contrast, antiapoptotic Bcl-xL induces transient permeability alterations in pure lipid membranes that have no consequences for the mitochondrial outer membrane but inhibit Bax membrane insertion. These differences in pore activity correlate with a distinct oligomeric state of Bax and Bcl-xL in membranes and can be reproduced in isolated mitochondria. Based on our findings, we propose new models for the mechanisms of action of Bax and Bcl-xL that relate their membrane activity to their opposing roles in apoptosis and beyond.
authors: German Cancer Research Center, BioQuant, Heidelberg, Germany.
authors: Stephanie
authors: S
authors: Bleicken
authors: Corinna
authors: C
authors: Wagner
authors: Ana J
authors: AJ
authors: García-Sáez
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002417:Cattle; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008954:Models, Biological; D016062:Porosity; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D053835:Unilamellar Liposomes / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D008051:Lipid Bilayers; D053835:Unilamellar Liposomes; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein