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


AUTHORS

Mandal TTirtha , Shin SSeungjin , Aluvila SSreevidya , Chen HCHui-Chen , Grieve CCarter , Choe JYJun-Yong , Cheng EHEmily H , Hustedt EJEric J , Oh KJKyoung Joon . Scientific reports. 2016 08 04; 6(). 30763

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 ‘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.