Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains
Details
Publication Year 2015-03-06, Volume 22, Issue #10, Page 1665-1675
Journal Title
Cell Death Differ
Publication Type
Journal Article
Abstract
Bak and Bax mediate apoptotic cell death by oligomerizing and forming a pore in the mitochondrial outer membrane. Both proteins anchor to the outer membrane via a C-terminal transmembrane domain, although its topology within the apoptotic pore is not known. Cysteine-scanning mutagenesis and hydrophilic labeling confirmed that in healthy mitochondria the Bak alpha9 segment traverses the outer membrane, with 11 central residues shielded from labeling. After pore formation those residues remained shielded, indicating that alpha9 does not line a pore. Bak (and Bax) activation allowed linkage of alpha9 to neighboring alpha9 segments, identifying an alpha9:alpha9 interface in Bak (and Bax) oligomers. Although the linkage pattern along alpha9 indicated a preferred packing surface, there was no evidence of a dimerization motif. Rather, the interface was invoked in part by Bak conformation change and in part by BH3:groove dimerization. The alpha9:alpha9 interaction may constitute a secondary interface in Bak oligomers, as it could link BH3:groove dimers to high-order oligomers. Moreover, as high-order oligomers were generated when alpha9:alpha9 linkage in the membrane was combined with alpha6:alpha6 linkage on the membrane surface, the alpha6-alpha9 region in oligomerized Bak is flexible. These findings provide the first view of Bak carboxy terminus (C terminus) membrane topology within the apoptotic pore.Cell Death and Differentiation advance online publication, 6 March 2015; doi:10.1038/cdd.2015.15.
Publisher
NPG
WEHI Research Division(s)
Molecular Genetics Of Cancer; Structural Biology
PubMed ID
25744027
NHMRC Grants
NHMRC/637337 NHMRC/1016701
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2015-03-09 09:45:34
Last Modified: 2015-11-11 09:52:12
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