Assembly of Bak homodimers into higher order homooligomers in the mitochondrial apoptotic pore.

ABSTRACT: 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 '?3/?5' interface, in which the C-termini of helices ?3 and ?5 are in close proximity between two neighboring Bak homodimers. This interface is observed concomitantly with the well-known '?6:?6' 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.

SUBMITTER: Mandal T 

PROVIDER: S-EPMC4973285 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature