Ensemble properties of bax determine its function
- Author(s)
- Robin, AY; Iyer, S; Birkinshaw, RW; Sandow, J; Wardak, A; Luo, CS; Shi, M; Webb, AI; Czabotar, PE; Kluck, RM; Colman, PM;
- Details
- Publication Year 2018-10,Volume 26,Issue #10,Page 1346-1359.e5
- Journal Title
- Structure
- Publication Type
- Journal Article
- Abstract
- BAX and BAK are essential mediators of intrinsic apoptosis that permeabilize the mitochondrial outer membrane. BAX activation requires its translocation from cytosol to mitochondria where conformational changes cause its oligomerization. To better understand the critical step of translocation, we examined its blockade by mutation near the C terminus (P168G) or by antibody binding near the N terminus. Similarities in the crystal structures of wild-type and BAX P168G but significant other differences suggest that cytosolic BAX exists as an ensemble of conformers, and that the distribution of conformers within the ensemble determines the different functions of wild-type and mutant proteins. We also describe the structure of BAX in complex with an antibody, 3C10, that inhibits cytosolic BAX by limiting exposure of the membrane-associating helix alpha9, as does the P168G mutation. Our data for both means of BAX inhibition argue for an allosteric model of BAX regulation that derives from properties of the ensemble of conformers.
- Publisher
- Cell Press
- Research Division(s)
- Structural Biology; Molecular Genetics Of Cancer; Systems Biology And Personalised Medicine
- PubMed ID
- 30122452
- Publisher's Version
- https://doi.org/10.1016/j.str.2018.07.006
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-08-27 09:10:44
Last Modified: 2018-10-11 01:16:26