The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site

被引：188
作者：
Moldoveanu, Tudor
Liu, Qian
Tocilj, Ante
Watson, Mark
Shore, Gordon
Gehring, Kalle
机构：
[1] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[2] GeminX Biotechnol Inc, Montreal, PQ H2X 4A5, Canada
来源：
MOLECULAR CELL | 2006年 / 24卷 / 05期
基金：
加拿大健康研究院;
关键词：
D O I：
10.1016/j.molcel.2006.10.014
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：
BAK/BAX-mediated mitochondrial outer-membrane permeabilization (MOMP) drives cell death during development and tissue homeostasis from zebrafish to humans. In most cancers, this pathway is inhibited by BCL-2 family antiapoptotic members, which bind and block the action of proapoptotic BCL proteins. We report the 1.5 angstrom crystal structure of calpain-proteolysed BAK, cBAK, to reveal a zinc binding site that regulates its activity via homodimerization. cBAK contains an occluded BH3 peptide binding pocket that binds a BID BH3 peptide only weakly. Nonetheless, cBAK requires activation by truncated BID to induce cytochrome c release in mitochondria isolated from bak/bax double-knockout mouse embryonic fibroblasts. The BAK-mediated MOMP is inhibited by low micromolar zinc levels. This inhibition is alleviated by mutation of the zinc-coordination site in BAK. Our results link directly the antiapoptotic effects of zinc to BAK.
引用
收藏
页码：677 / 688
页数：12
相关论文
共 59 条
[1]   Zinc coordination sphere in biochemical zinc sites [J].
Auld, DS .
BIOMETALS, 2001, 14 (3-4) :271-313
[2]   Regulation of apoptosis by endoplasmic reticulum pathways [J].
Breckenridge, DG ;
Germain, M ;
Mathai, JP ;
Nguyen, M ;
Shore, GC .
ONCOGENE, 2003, 22 (53) :8608-8618
[3]  
Brunger AT, 1998, ACTA CRYSTALLOGR D, V54, P905, DOI 10.1107/s0907444998003254
[4]   Cleavage of Bax to p18 Bax accelerates stress-induced apoptosis, and a cathepsin-like protease may rapidly degrade p18 Bax [J].
Cao, XF ;
Deng, XM ;
May, WS .
BLOOD, 2003, 102 (07) :2605-2614
[5]   Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members [J].
Certo, Michael ;
Moore, Victoria Del Gaizo ;
Nishino, Mari ;
Wei, Guo ;
Korsmeyer, Stanley ;
Armstrong, Scott A. ;
Letai, Anthony .
CANCER CELL, 2006, 9 (05) :351-365
[6]   Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function [J].
Chen, L ;
Willis, SN ;
Wei, A ;
Smith, BJ ;
Fletcher, JI ;
Hinds, MG ;
Colman, PM ;
Day, CL ;
Adams, JM ;
Huang, DCS .
MOLECULAR CELL, 2005, 17 (03) :393-403
[7]   Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion [J].
Chen, M ;
He, HP ;
Zhan, SX ;
Krajewski, S ;
Reed, JC ;
Gottlieb, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (33) :30724-30728
[8]   Solution structure of BID, an intracellular amplifier of apoptotic signaling [J].
Chou, JJ ;
Li, HL ;
Salvesen, GS ;
Yuan, JY ;
Wagner, G .
CELL, 1999, 96 (05) :615-624
[9]   The BCL2 family: Regulators of the cellular life-or-death switch [J].
Cory, S ;
Adams, JM .
NATURE REVIEWS CANCER, 2002, 2 (09) :647-656
[10]   Cell death: Critical control points [J].
Danial, NN ;
Korsmeyer, SJ .
CELL, 2004, 116 (02) :205-219
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