Regulated targeting of BAX to mitochondria.
Regulated targeting of BAX to mitochondria.
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DOI：
10.1083/jcb.143.1.207
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发表时间：
1998-10-05
影响因子：
7.8
通讯作者：
Shore, G C
中科院分区：
文献类型：
--
作者：
Goping, I S;Gross, A;Lavoie, J N;Nguyen, M;Jemmerson, R;Roth, K;Korsmeyer, S J;Shore, G C
促凋亡蛋白Bax在其COOH末端含有一个预测的跨膜结构域。在未受刺激的细胞中，Bax定位于胞浆中，并与包括线粒体在内的细胞内膜结合在一起，但在死亡信号发出后插入线粒体膜。在没有死亡信号的情况下，这种未能插入线粒体膜的现象与NH2-末端结构域抑制Bax的跨膜信号锚功能有关。靶向可以通过删除结构域或用bcl-2的跨膜片段替换bax来实现。在受刺激的细胞中，Bax的NH2末端的贡献与蛋白质膜插入后该结构域的进一步暴露有关。半胱氨酸天冬氨酸氨基转移酶抑制剂ZVAD-FMK在体内部分阻断了线粒体膜上Bax的插入，这与凋亡细胞提取物在体外支持线粒体靶向Bax的能力是一致的，依赖于半胱氨酸酶的激活(S)。综上所述，我们的结果表明，Bax对线粒体的调控靶向反应死亡信号是由Bax多肽中的离散结构域介导的。一个或多个caspase的作用可能反映了这种受调控靶向的启动和/或放大。
The proapoptotic protein BAX contains a single predicted transmembrane domain at its COOH terminus. In unstimulated cells, BAX is located in the cytosol and in peripheral association with intracellular membranes including mitochondria, but inserts into mitochondrial membranes after a death signal. This failure to insert into mitochondrial membrane in the absence of a death signal correlates with repression of the transmembrane signal-anchor function of BAX by the NH2-terminal domain. Targeting can be instated by deleting the domain or by replacing the BAX transmembrane segment with that of BCL-2. In stimulated cells, the contribution of the NH2 terminus of BAX correlates with further exposure of this domain after membrane insertion of the protein. The peptidyl caspase inhibitor zVAD-fmk partly blocks the stimulated mitochondrial membrane insertion of BAX in vivo, which is consistent with the ability of apoptotic cell extracts to support mitochondrial targeting of BAX in vitro, dependent on activation of caspase(s). Taken together, our results suggest that regulated targeting of BAX to mitochondria in response to a death signal is mediated by discrete domains within the BAX polypeptide. The contribution of one or more caspases may reflect an initiation and/or amplification of this regulated targeting.