Open AccessAssembly of Bak homodimers into higher order homooligomers in the mitochondrial apoptotic pore
Author(s) -
Tirtha Mandal,
Sue Shin,
Sreevidya Aluvila,
Hui-Chen Chen,
Carter Grieve,
Juhui Choe,
Emily H. Cheng,
Eric J. Hustedt,
Kyoung Joon Oh
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep30763
Subject(s) - intermembrane space , mitochondrial intermembrane space , topology (electrical circuits) , electron paramagnetic resonance , cytochrome c , mitochondrion , biophysics , inner mitochondrial membrane , bilayer , lipid bilayer , chemistry , microbiology and biotechnology , bacterial outer membrane , membrane , biology , physics , biochemistry , gene , nuclear magnetic resonance , mathematics , escherichia coli , combinatorics
In mitochondrial apoptosis, Bak is activated by death signals to form pores of unknown structure on the mitochondrial outer membrane via homooligomerization. Cytochrome c and other apoptotic factors are released from the intermembrane space through these pores, initiating downstream apoptosis events. Using chemical crosslinking and double electron electron resonance (DEER)-derived distance measurements between specific structural elements in Bak, here we clarify how the Bak pore is assembled. We propose that previously described BH3-in-groove homodimers (BGH) are juxtaposed via the ‘α3/α5’ interface, in which the C-termini of helices α3 and α5 are in close proximity between two neighboring Bak homodimers. This interface is observed concomitantly with the well-known ‘α6:α6’ interface. We also mapped the contacts between Bak homodimers and the lipid bilayer based on EPR spectroscopy topology studies. Our results suggest a model for the lipidic Bak pore, whereby the mitochondrial targeting C-terminal helix does not change topology to accommodate the lining of the pore lumen by BGH.