Clavería Cristina, Caminero Eva, Martínez-A Carlos, Campuzano Sonsoles, Torres Miguel
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, CSIC-UAM, Campus de Cantoblanco, E-28049 Madrid, Spain.
EMBO J. 2002 Jul 1;21(13):3327-36. doi: 10.1093/emboj/cdf354.
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.
Grim编码果蝇程序性细胞死亡所需的一种蛋白质。Grim的N端通过破坏IAP对胱天蛋白酶的阻断来诱导细胞凋亡；然而，N端缺失的Grim仍保留促凋亡活性。我们描述了GH3，这是一个由15个氨基酸组成的Grim内部结构域，其促凋亡活性绝对需要该结构域，并且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同源区域。预测GH3结构域以及Reaper和Sickle中的同源区域构成为两亲性α螺旋。在细胞凋亡诱导过程中，Grim以一种依赖于GH3但不依赖于N端和胱天蛋白酶活性的方式与线粒体和细胞色素c共定位。当Grim在体内过表达时，N端和GH3结构域同样必要，并协同诱导细胞凋亡。因此，Grim的N端和GH3结构域激活独立的凋亡途径，这些途径协同作用以有效地诱导程序性细胞死亡。
