title: Small molecules reveal an alternative mechanism of Bax activation.
abstract: The pro-apoptotic protein Bax commits a cell to death by permeabilizing the mitochondrial outer membrane (MOM). To obtain small-molecule probes for elucidating the molecular mechanism(s) of Bax activation, we screened for compounds that induced Bax-mediated liposome permeabilization. We identified five structurally different small molecules that promoted both Bax targeting to and oligomerization at membranes. All five compounds initiated Bax oligomerization in the absence of membranes by a mechanism unlike Bax activation by Bcl-2 homology 3 domain (BH3) proteins. Some of the compounds induced Bax/Bak-dependent apoptosis in cells. Activation of Bax by the most active compound was poorly inhibited by the anti-apoptotic protein Bcl-XL and requires a cysteine residue at position 126 of Bax that is not required for activation by BH3 proteins. Our results reveal a novel pathway for Bax activation independent of pro-apoptotic BH3 proteins that may have important implications for the regulation of Bax activity in cells.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada, L8S 4L8 Department of Biological Sciences, Sunnybrook Research Institute, University of Toronto, ON, Canada, M4N 3M5.
authors.forename: Hetal
authors.initials: H
authors.lastname: Brahmbhatt
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada, M5G 0A3.
authors.forename: David
authors.initials: D
authors.lastname: Uehling
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada, M5G 0A3.
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada, L8S 4L8.
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada, L8S 4L8 Department of Biological Sciences, Sunnybrook Research Institute, University of Toronto, ON, Canada, M4N 3M5 david.andrews@sri.utoronto.ca.
authors.forename: David
authors.initials: D
authors.lastname: Andrews
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C474007:Bax protein (53-86); D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries; D051028:bcl-2-Associated X Protein
keywords: Bax activators; Bax oligomerization; apoptosis; cysteine; mechanism probes; membrane permeabilization