BAX Activation: Mutations Near Its Proposed Non-canonical BH3 Binding Site Reveal Allosteric Changes Controlling Mitochondrial Association
- Author(s)
- Dengler, MA; Robin, AY; Gibson, L; Li, MX; Sandow, JJ; Iyer, S; Webb, AI; Westphal, D; Dewson, G; Adams, JM;
- Details
- Publication Year 2019-04-09,Volume 27,Issue #2,Page 359-373 e6
- Journal Title
- Cell Reports
- Publication Type
- Journal Article
- Abstract
- To elicit apoptosis, BAX metamorphoses from an inert cytosolic monomer into homo-oligomers that permeabilize the mitochondrial outer membrane (MOM). A long-standing puzzle is that BH3 domains apparently activate BAX by not only its canonical groove but also a proposed site involving helices alpha1 and alpha6. Our mutagenesis studies reveal that late steps like oligomerization require activation through the groove but probably not earlier steps like MOM association. Conversely, alpha1 or alpha6 obstruction and alanine mutagenesis scanning implicate these helices early in BAX activation. The alpha1 and alpha6 mutations lowered BH3 binding, altered the BAX conformation, and reduced its MOM translocation and integration; their exposure of the BAX alpha1-alpha2 loop allosterically sequestered its alpha9 membrane anchor in the groove. The crystal structure of an alpha6 mutant revealed additional allosteric effects. The results suggest that the alpha1 and alpha6 region drives MOM association and integration, whereas groove binding favors subsequent steps toward oligomerization.
- Publisher
- Springer Nature
- Research Division(s)
- Blood Cells And Blood Cancer; Structural Biology; Ubiquitin Signalling; Advanced Technology And Biology
- PubMed ID
- 30970242
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2019.03.040
- Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2019.03.040- NHMRC Grants
- NHMRC/1016701, NHMRC/1078924,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-04-12 10:26:45
Last Modified: 2019-04-12 11:36:40