Characterization of an alternative BAK-binding site for BH3 peptides

doi:10.1038/s41467-020-17074-y

	Characterization of an alternative BAK-binding site for BH3 peptides
	Ye, Kaiqin 5,6; Meng, Wei X.3,4; Sun, Hongbin 2; Wu, Bo 1; Chen, Meng 5,6; Pang, Yuan-Ping 3; Gao, Jia 5,6; Wang, Hongzhi 5,6; Wang, Junfeng 1; Kaufmann, Scott H.3,4
刊名	NATURE COMMUNICATIONS
	2020-07-03
卷号	11
ISSN号	2041-1723
DOI	10.1038/s41467-020-17074-y
通讯作者	Kaufmann, Scott H.(Kaufmann.Scott@mayo.edu) ; Dai, Haiming(daih@cmpt.ac.cn)
英文摘要	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 alpha 4, alpha 6, and alpha 7 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. Mitochondrial apoptosis is controlled by BCL2 family proteins, and the BH3-only proteins often act as sensors that transmit apoptotic signals. Here the authors show how the BH3-only proteins BMF and HRK can directly activate the BCL2 protein BAK and interact with BAK through an alternative binding groove.
资助项目	National Natural Science Foundation of China[81572948] ; National Natural Science Foundation of China[21772201] ; National Natural Science Foundation of China[21703254] ; Hundred-Talents Program of Chinese Academy of Science ; innovative program of Development Foundation of Hefei Center for Physical Science and Technology[2018CXFX007] ; Hefei Foreign Cooperation Project[ZR201801020002] ; President Foundation of Hefei Institutes of Physical Science of Chinese Academy of Sciences[YZJJ201623]
WOS关键词	BH3-ONLY PROTEIN PUMA ; CONFORMATIONAL-CHANGES ; MEMBRANE INSERTION ; ACTIVATION ; APOPTOSIS ; DOMAINS ; BIM ; SENSITIVITY ; INTERFACE ; BMF
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000546623500001
资助机构	National Natural Science Foundation of China ; Hundred-Talents Program of Chinese Academy of Science ; innovative program of Development Foundation of Hefei Center for Physical Science and Technology ; Hefei Foreign Cooperation Project ; President Foundation of Hefei Institutes of Physical Science of Chinese Academy of Sciences
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/71203]
专题	中国科学院合肥物质科学研究院
通讯作者	Kaufmann, Scott H.; Dai, Haiming
作者单位	1.Chinese Acad Sci, HFIPS, High Field Magnet Lab, CAS Key Lab High Magnet Field & Ion Beam Phys Bio, Hefei 230031, Peoples R China 2.Zhenzhou Univ Light Ind, Sch Food & Biol Engn, Zhenzhou 450002, Peoples R China 3.Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA 4.Mayo Clin, Div Oncol Res, Rochester, MN 55905 USA 5.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Peoples R China 6.Chinese Acad Sci, Hefei Inst Phys Sci, Ctr Med Phys & Technol, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Peoples R China
推荐引用方式 GB/T 7714	Ye, Kaiqin,Meng, Wei X.,Sun, Hongbin,et al. Characterization of an alternative BAK-binding site for BH3 peptides[J]. NATURE COMMUNICATIONS,2020,11.
APA	Ye, Kaiqin.,Meng, Wei X..,Sun, Hongbin.,Wu, Bo.,Chen, Meng.,...&Dai, Haiming.(2020).Characterization of an alternative BAK-binding site for BH3 peptides.NATURE COMMUNICATIONS,11.
MLA	Ye, Kaiqin,et al."Characterization of an alternative BAK-binding site for BH3 peptides".NATURE COMMUNICATIONS 11(2020).