Disordered clusters of Bak dimers rupture mitochondria during apoptosis

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

来源：eLife, 2017, 6: e19944.

DOI：10.7554/eLife.19944

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.

• 出版日期2017-2-6
• 单位河北医科大学; 迪肯大学