Journal article

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

Sweta Iyer, Rachel T Uren, Michael A Dengler, Melissa X Shi, Etsuko Uno, Jerry M Adams, Grant Dewson, Ruth M Kluck

Cell Death and Disease | NATURE PUBLISHING GROUP | Published : 2020

Abstract

BAK and BAX, which drive commitment to apoptosis, are activated principally by certain BH3-only proteins that bind them and trigger major rearrangements. One crucial conformation change is exposure of their BH3 domain which allows BAK or BAX to form homodimers, and potentially to autoactivate other BAK and BAX molecules to ensure robust pore formation and cell death. Here, we test whether full-length BAK or mitochondrial BAX that are specifically activated by antibodies can then activate other BAK or BAX molecules. We found that antibody-activated BAK efficiently activated BAK as well as mitochondrial or cytosolic BAX, but antibody-activated BAX unexpectedly proved a poor activator. Notably,..

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Grants

Awarded by National Health and Medical Research Council, Australia


Awarded by Leukemia and Lymphoma Society, United States


Awarded by Australian Government Independent Research Institute Infrastructure Support Scheme


Funding Acknowledgements

We thank Peter Colman for calculations of shape complementarity and buried surface area in core dimer structures. We also thank Amber Alsop, Colin Hockings, and Jason Brouwer for advice on experiments and for useful discussions. This work was supported by program grant 1016701 (to J.M.A. and R.M.K.) and project grant 1078924 (to G.D.) from the National Health and Medical Research Council, Australia, SCOR grant 7001-13 from the Leukemia and Lymphoma Society, United States (to J.M.A. and R.M.K.), fellowship (to S.I.) from the Lady Tata Memorial Trust and project grant (to S.I.) from The Jack Brockhoff Foundation and Marian and E.H. Flack Trust Early Career Research Grant, as well as operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000220) and the Victorian State Government Operational Infrastructure Support Program. Supplementary information is available at Cell Death and Disease website.