Characterization of an alternative BAK-binding site for BH3 peptides

Kaiqin Ye, Wei X. Meng, Hongbin Sun, Bo Wu, Meng Chen, Yuan-Ping Pang, Jia Gao, Hongzhi Wang, Junfeng Wang, Scott H. Kaufmann () and Haiming Dai ()
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Kaiqin Ye: Chinese Academy of Sciences
Wei X. Meng: Mayo Clinic
Hongbin Sun: Zhenzhou University of Light Industry
Bo Wu: HFIPS, Chinese Academy of Sciences
Meng Chen: Chinese Academy of Sciences
Yuan-Ping Pang: Mayo Clinic
Jia Gao: Chinese Academy of Sciences
Hongzhi Wang: Chinese Academy of Sciences
Junfeng Wang: HFIPS, Chinese Academy of Sciences
Scott H. Kaufmann: Mayo Clinic
Haiming Dai: Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Many cellular stresses are transduced into apoptotic signals through modification or up-regulation of the BH3-only subfamily of BCL2 proteins. Through direct or indirect mechanisms, these proteins activate BAK and BAX to permeabilize the mitochondrial outer membrane. While the BH3-only proteins BIM, PUMA, and tBID have been confirmed to directly activate BAK through its canonical BH3 binding groove, whether the BH3-only proteins BMF, HRK or BIK can directly activate BAK is less clear. Here we show that BMF and HRK bind and directly activate BAK. Through NMR studies, site-directed mutagenesis, and advanced molecular dynamics simulations, we also find that BAK activation by BMF and possibly HRK involves a previously unrecognized binding groove formed by BAK α4, α6, and α7 helices. Alterations in this groove decrease the ability of BMF and HRK to bind BAK, permeabilize membranes and induce apoptosis, suggesting a potential role for this BH3-binding site in BAK activation.

Date: 2020
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DOI: 10.1038/s41467-020-17074-y

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