Journal article

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

Mark Xiang Li, Iris KL Tan, Stephen B Ma, Colin Hockings, Tobias Kratina, Michael A Dengler, Amber E Alsop, Ruth M Kluck, Grant Dewson

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2017

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 (α2-5..

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Grants

Awarded by National Health and Medical Research Council


Awarded by Australian Research Council


Awarded by Victorian State Government


Funding Acknowledgements

We thank Kristen Scicluna for technical assistance and Peter Colman, Sweta Iyer, and Peter Czabotar for helpful discussions and advice on the manuscript. This work was supported by National Health and Medical Research Council Grants 1059290 and 1078924, Australian Research Council Fellowship FT100100791 (to G.D.), and operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support 9000220.