A stapled BID BH3 helix directly binds and activates BAX

被引:320
作者
Walensky, Loren D.
Pitter, Kenneth
Morash, Joel
Oh, Kyoung Joon
Barbuto, Scott
Fisher, Jill
Smith, Eric
Verdine, Gregory L.
Korsmeyer, Stanley J.
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA
[4] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA
[5] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[6] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA
关键词
D O I
10.1016/j.molcel.2006.08.020
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
BAX is a multidomain proapoptotic BCL-2 family protein that resides in the cytosol until activated by an incompletely understood trigger mechanism, which facilitates BAX translocation to mitochondria and downstream death events. Whether BAX is activated by direct contact with select BH3-only members of the BCL-2 family is highly debated. Here we detect and quantify a direct binding interaction between BAX and a hydrocarbon-stapled BID BH3 domain, which triggers the functional activation of BAX at nanomolar doses in vitro. Chemical reinforcement of BID BH3 alpha helicity was required to reveal the direct BID BH3-BAX association. We confirm the specificity of this BH3 interaction by characterizing a stapled BAD BH3 peptide that interacts with antiapoptotic BCL-X-L but does not bind or activate BAX. We further demonstrate that membrane targeting of stapled BID BH3 optimizes its ability to activate BAX, supporting a model in which BID directly engages BAX to trigger mitochondrial apoptosis.
引用
收藏
页码:199 / 210
页数:12
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