title: Lipidic pore formation by the concerted action of proapoptotic BAX and tBID.
abstract: BCL-2 homology 3 (BH3)-only proteins of the BCL-2 family such as tBID and BIM(EL) assist BAX-type proteins to breach the permeability barrier of the outer mitochondrial membrane, thereby allowing cytoplasmic release of cytochrome c and other active inducers of cell death normally confined to the mitochondrial inter-membrane space. However, the exact mechanism by which tBID and BIM(EL) aid BAX and its close homologues in this mitochondrial protein release remains enigmatic. Here, using pure lipid vesicles, we provide evidence that tBID acts in concert with BAX to 1) form large membrane openings through both BH3-dependent and BH3-independent mechanisms, 2) cause lipid transbilayer movement concomitant with membrane permeabilization, and 3) disrupt the lipid bilayer structure of the membrane by promoting positive monolayer curvature stress. None of these effects were observed with BAX when BIM(EL) was substituted for tBID. Based on these data, we propose a novel model in which tBID assists BAX not only via protein-protein but also via protein-lipid interactions to form lipidic pore-type non-bilayer structures in the outer mitochondrial membrane through which intermembrane prodeath molecules exit mitochondria during apoptosis.
authors.affiliation: Unidad de Biofísica (Centro Mixto Consejo Superior de Investigaciones Cientificas-Universidad del Pais Vasco/Euskal Herriko Unibertsitatea), Universidad del Pais Vasco/Euskal Herriko Unibertsitatea, P. O. Box 644, 48080 Bilbao, Spain.
authors.forename: Oihana
authors.initials: O
authors.lastname: Terrones
authors.forename: Bruno
authors.initials: B
authors.lastname: Antonsson
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: Jihua
authors.initials: J
authors.lastname: Liu
authors.forename: Ray M
authors.initials: RM
authors.lastname: Lee
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Gorka
authors.initials: G
authors.lastname: Basañez
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008027:Light; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D012542:Scattering, Radiation; D013997:Time Factors; D051028:bcl-2-Associated X Protein
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494828:Bax protein, rat; C494816:Bid protein, rat; D002352:Carrier Proteins; D008051:Lipid Bilayers; D008055:Lipids; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c