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

作者：Mandal Tirtha; Shin Seungjin; Aluvila Sreevidya; Chen Hui Chen; Grieve Carter; Choe Jun Yong; Cheng Emily H; Hustedt Eric J; Oh Kyoung Joon^*

来源：Scientific Reports, 2016, 6(1): 30763.

DOI：10.1038/srep30763

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

• 出版日期2016-8-4