Jun 22, 2016

Disordered clusters of Bak dimers rupture mitochondria during apoptosis

BioRxiv : the Preprint Server for Biology
Rachel T UrenRuth M Kluck


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 aggregation. Together, our biochemical data and mathematical modelling show that Bak dimers form disordered, compact clusters to generate lipidic pores. These findings provide a molecular explanation for the observed structural heterogeneity of the apoptotic pore.

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Mentioned in this Paper

N-Bak Protein
Macromolecular Alteration
Bax protein (53-86)
Protein Aggregation, Pathological

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