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Disordered clusters of Bak dimers rupture mitochondria during apoptosis

Uren, Rachel T, O'Hely, Martin, Iyer, Sweta, Bartolo, Ray, Shi, Melissa X, Brouwer, Jason M, Alsop, Amber E, Dewson, Grant and Kluck, Ruth M 2017, Disordered clusters of Bak dimers rupture mitochondria during apoptosis, eLife, vol. 6, pp. 1-23, doi: 10.7554/eLife.19944.

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Title Disordered clusters of Bak dimers rupture mitochondria during apoptosis
Author(s) Uren, Rachel T
O'Hely, Martin
Iyer, Sweta
Bartolo, Ray
Shi, Melissa X
Brouwer, Jason M
Alsop, Amber E
Dewson, Grant
Kluck, Ruth M
Journal name eLife
Volume number 6
Article ID e19944
Start page 1
End page 23
Total pages 23
Publisher eLife Sciences Publications
Place of publication Cambridge, Eng.
Publication date 2017-02-06
ISSN 2050-084X
2050-084X
Keyword(s) Bak
Bcl-2 proteins
Apoptotic pore
Biophysics
Cell biology
Cell death
Disordered cluster
Human
Oligomer
Structural biology
Science & technology
Life sciences & biomedicine
Biology
Life sciences & biomedicine - other topics
Prosurvival BCL-2 proteins
Pore formation
Outer membrane
BH3 domain
Cell death
Conformational changes
Transmembrane domains
Proapoptotic Bax
Image analysis
Latch domains
Summary 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.
Language eng
DOI 10.7554/eLife.19944
Field of Research 110199 Medical Biochemistry and Metabolomics not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2017, Uren et al
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30093517

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Created: Thu, 06 Apr 2017, 11:33:58 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.