Disordered clusters of Bak dimers rupture mitochondria during apoptosis

Rachel T Uren; Martin O’Hely; Sweta Iyer; Ray Bartolo; Melissa X Shi; Jason M Brouwer; Amber E Alsop; Grant Dewson; Ruth M Kluck

doi:10.7554/eLife.19944

eLife (Feb 2017)

Disordered clusters of Bak dimers rupture mitochondria during apoptosis

Rachel T Uren,
Martin O’Hely,
Sweta Iyer,
Ray Bartolo,
Melissa X Shi,
Jason M Brouwer,
Amber E Alsop,
Grant Dewson,
Ruth M Kluck

Affiliations

Rachel T Uren: ORCiD; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Martin O’Hely: ORCiD; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Sweta Iyer: ORCiD; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Ray Bartolo: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Melissa X Shi: ORCiD; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Jason M Brouwer: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Amber E Alsop: ORCiD; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Grant Dewson: ORCiD; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Ruth M Kluck: ORCiD; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia

DOI: https://doi.org/10.7554/eLife.19944
Journal volume & issue: Vol. 6

Abstract

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During apoptosis, Bak and Bax undergo major conformational change and form symmetric dimers that coalesce to perforate the mitochondrial outer membrane via an unknown mechanism. We have employed cysteine labelling and linkage analysis to the full length of Bak in mitochondria. This comprehensive survey showed that in each Bak dimer the N-termini are fully solvent-exposed and mobile, the core is highly structured, and the C-termini are flexible but restrained by their contact with the membrane. Dimer-dimer interactions were more labile than the BH3:groove interaction within dimers, suggesting there is no extensive protein interface between dimers. In addition, linkage in the mobile Bak N-terminus (V61C) specifically quantified association between dimers, allowing mathematical simulations of dimer arrangement. Together, our data show that Bak dimers form disordered clusters to generate lipidic pores. These findings provide a molecular explanation for the observed structural heterogeneity of the apoptotic pore.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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