文章基本信息

标题：BAK α6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove
本地全文：下载
作者：Mark Xiang Li ; Iris K. L. Tan ; Stephen B. Ma 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：29
页码：7629-7634
DOI：10.1073/pnas.1702453114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：BAK and BAX are the essential effectors of apoptosis because without them a cell is resistant to most apoptotic stimuli. BAK and BAX undergo conformation changes to homooligomerize then permeabilize the mitochondrial outer membrane during apoptosis. How BCL-2 homology 3 (BH3)-only proteins bind to activate BAK and BAX is unclear. We report that BH3-only proteins bind inactive full-length BAK at mitochondria and then dissociate following exposure of the BAK BH3 and BH4 domains before BAK homodimerization. Using a functional obstructive labeling approach, we show that activation of BAK involves important interactions of BH3-only proteins with both the canonical hydrophobic binding groove (α2–5) and α6 at the rear of BAK, with interaction at α6 promoting an open groove to receive a BH3-only protein. Once activated, how BAK homodimers multimerize to form the putative apoptotic pore is unknown. Obstructive labeling of BAK beyond the BH3 domain and hydrophobic groove did not inhibit multimerization and mitochondrial damage, indicating that critical protein–protein interfaces in BAK self-association are limited to the α2–5 homodimerization domain.
关键词：apoptosis ; BAK ; BAX ; BH3-only protein ; mitochondria