BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAX

被引：248

作者：

Gavathiotis, Evripidis ^{[1
,2
,3
,4
]}

Reyna, Denis E. ^{[1
,2
,3
,4
]}

Davis, Marguerite L. ^{[1
,2
,3
,4
]}

Bird, Gregory H. ^{[1
,2
,3
,4
]}

Walensky, Loren D. ^{[1
,2
,3
,4
]}

机构：

[1] Harvard Univ, Sch Med, Dept Pediat Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Program Canc Chem Biol, Dana Farber Canc Inst, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

来源：

MOLECULAR CELL | 2010年 / 40卷 / 03期

基金：

美国国家卫生研究院;

关键词：

MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; STABILIZED ALPHA-HELICES; BH3-ONLY PROTEINS; CONFORMATIONAL-CHANGE; BH3; DOMAINS; APOPTOTIC ACTIVITY; IN-VIVO; BCL-2; BIM; OLIGOMERIZATION;

D O I：

10.1016/j.molcel.2010.10.019

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 proapoptotic BCL-2 family member that lies dormant in the cytosol until converted into a killer protein in response to cellular stress. Having recently identified the elusive trigger site for direct BAX activation, we now delineate by NMR and biochemical methods the essential allosteric conformational changes that transform ligand-triggered BAX into a fully activated monomer capable of propagating its own activation. Upon BAX engagement by a triggering BH3 helix, the unstructured loop between a helices 1 and 2 is displaced, the carboxy-terminal helix 9 is mobilized for membrane translocation, and the exposed BAX BH3 domain propagates the death signal through an auto activating interaction with the trigger site of inactive BAX monomers. Our structure-activity analysis of this seminal apoptotic process reveals pharmacologic opportunities to modulate cell death by interceding at key steps of the BAX activation pathway.

引用

页码：481 / 492

页数：12

共 64 条

[1] Rax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis [J].