GH3, a novel proapoptotic domain in Drosophila Grim, promotes a mitochondrial death pathway
GH3, a novel proapoptotic domain in Drosophila Grim, promotes a mitochondrial death pathway
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DOI：
10.1093/emboj/cdf354
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发表时间：
2002-07-01
期刊：
影响因子：
11.4
通讯作者：
Torres, M
中科院分区：
文献类型：
--
作者：
Clavería, C;Caminero, E;Torres, M
GRIM编码果蝇细胞程序性死亡所需的一种蛋白质。GRIM N-末端通过破坏IAP对caspase的阻断而诱导细胞凋亡；然而，N-末端缺失的GRIM保持促凋亡活性。我们描述了GH3，一个15个氨基酸的内部Grim结构域，是其促凋亡活性所必需的，当与异源载体蛋白融合时足以诱导细胞死亡。果蝇促凋亡蛋白Reaper和Sickle中存在一个GH3同源区。据预测，在Reaper和Sickle中的GH3结构域及其同源区被预测为两亲性α-螺旋。在诱导细胞凋亡的过程中，Grim与线粒体和细胞色素c以一种GH3依赖但N端和caspase活性不依赖的方式共存。当Grim在体内过表达时，N端和GH3结构域都是同样必要的，并协同诱导细胞凋亡。N-末端和GH3Grim结构域因此激活独立的凋亡途径，这些途径协同有效地诱导细胞程序性死亡。
Grim encodes a protein required for programmed cell death in Drosophila. The Grim N-terminus induces apoptosis by disrupting IAP blockage of caspases; however, N-terminally-deleted Grim retains pro apoptotic activity. We describe GH3, a 15 amino acid internal Grim domain absolutely required for its proapoptotic activity and sufficient to induce cell death when fused to heterologous carrier proteins. A GH3 homology region is present in the Drosophila proapoptotic proteins Reaper and Sickle. The GH3 domain and the homologous regions in Reaper and Sickle are predicted to be structured as amphipathic alpha-helixes. During apoptosis induction, Grim colocalizes with mitochondria and cytochrome c in a GH3-dependent but N-terminal- and caspase activity-independent manner. When Grim is overexpressed in vivo, both the N-terminal and the GH3 domains are equally necessary, and cooperate for apoptosis induction. The N-terminal and GH3 Grim domains thus activate independent apoptotic pathways that synergize to induce programmed cell death efficiently.