BAK alpha6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove
- Author(s)
- Li, MX; Tan, IKL; Ma, SB; Hockings, C; Kratina, T; Dengler, MA; Alsop, AE; Kluck, RM; Dewson, G;
- Details
- Publication Year 2017-07-18,Volume 114,Issue #29,Page 7629-7634
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type
- Journal Article
- Abstract
- BAK and BAX are the essential effectors of apoptosis because without them a cell is resistant to most apoptotic stimuli. BAK and BAX undergo conformation changes to homooligomerize then permeabilize the mitochondrial outer membrane during apoptosis. How BCL-2 homology 3 (BH3)-only proteins bind to activate BAK and BAX is unclear. We report that BH3-only proteins bind inactive full-length BAK at mitochondria and then dissociate following exposure of the BAK BH3 and BH4 domains before BAK homodimerization. Using a functional obstructive labeling approach, we show that activation of BAK involves important interactions of BH3-only proteins with both the canonical hydrophobic binding groove (alpha2-5) and alpha6 at the rear of BAK, with interaction at alpha6 promoting an open groove to receive a BH3-only protein. Once activated, how BAK homodimers multimerize to form the putative apoptotic pore is unknown. Obstructive labeling of BAK beyond the BH3 domain and hydrophobic groove did not inhibit multimerization and mitochondrial damage, indicating that critical protein-protein interfaces in BAK self-association are limited to the alpha2-5 homodimerization domain.
- Publisher
- Rockefeler Uni Press
- Research Division(s)
- Cell Signalling And Cell Death; Molecular Immunology; Molecular Genetics Of Cancer
- PubMed ID
- 28673969
- Link To PubMed Central Version
- https://www.ncbi.nlm.nih/pmc/articles/PMC5530671/
- Publisher's Version
- https://doi.org/10.1073/pnas.1702453114
- NHMRC Grants
- NHMRC/1059290, NHMRC/1078924,
- ARC Grants
- ARC/FT100100791,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-07-26 12:48:12
Last Modified: 2018-07-04 11:38:56