TY - JOUR
T1 - Characterization of an alternative BAK-binding site for BH3 peptides
AU - Ye, Kaiqin
AU - Meng, Wei X.
AU - Sun, Hongbin
AU - Wu, Bo
AU - Chen, Meng
AU - Pang, Yuan Ping
AU - Gao, Jia
AU - Wang, Hongzhi
AU - Wang, Junfeng
AU - Kaufmann, Scott H.
AU - Dai, Haiming
N1 - Funding Information:
This work is supported by the National Natural Science Foundation of China (no. 81572948, no. 21772201, no. 21703254), the Hundred-Talents Program of Chinese Academy of Science to Haiming Dai, the innovative program of Development Foundation of Hefei Center for Physical Science and Technology (2018CXFX007), Hefei Foreign Cooperation Project (ZR201801020002), the Grant of the President Foundation of Hefei Institutes of Physical Science of Chinese Academy of Sciences (YZJJ201623). We thank the High Magnetic Field Laboratory of Chinese Academy of Sciences at Hefei for recording the NMR spectra and Dr. S. Yun from the Moffitt Cancer Center for the doxycycline inducible plasmid.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-17074-y
DO - 10.1038/s41467-020-17074-y
M3 - Article
C2 - 32620849
AN - SCOPUS:85087399055
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3301
ER -