BAK alpha 6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove

作者：Li Mark Xiang; Tan Iris K L; Ma Stephen B; Hockings Colin; Kratina Tobias; Dengler Michael A; Alsop Amber E; Kluck Ruth M; Dewson Grant

来源：Proceedings of the National Academy of Sciences, 2017, 114(29): 7629-7634.

DOI：10.1073/pnas.1702453114

• apoptosis
• BAK
• BAX
• BH3-only protein
• mitochondria

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 homo-dimerization. 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 (alpha 2-5) and alpha 6 at the rear of BAK, with interaction at alpha 6 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 alpha 2-5 homodimerization domain.

• 出版日期2017-7-18
• 单位河北医科大学