四个基因egl 1, ced-9, ced-4 和ced 3的互相作用控制线虫(C. elegan)的细胞凋亡。最新工作揭示了CED-4/CED-9 复合体的晶体结构。这一结构中, 一个CED-9分子结合CED-4 不对称的二聚体, 但只识别二个CED-4 分子当中的一个。EGL-1引发CED-9构象变化, 从而导致CED-4二聚体从CED-9离解的CED-9 上。被释放的CED-4 二聚体进一步形成四聚物促进CED-3 的激活。 这一研究通过分析蛋白复合体的结构提示了细胞凋亡的关键调控环节。
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Structure of the CED-4?CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans
Nieng Yan1, Jijie Chai1, Eui Seung Lee2,3, Lichuan Gu1, Qun Liu4, Jiaqing He5, Jia-Wei Wu1, David Kokel2, Huilin Li5, Quan Hao4, Ding Xue2 and Yigong Shi1
Interplay among four genes—egl-1, ced-9, ced-4 and ced-3—controls the onset of programmed cell death in the nematode Caenorhabditis elegans. Activation of the cell-killing protease CED-3 requires CED-4. However, CED-4 is constitutively inhibited by CED-9 until its release by EGL-1. Here we report the crystal structure of the CED-4?CED-9 complex at 2.6 ? resolution, and a complete reconstitution of the CED-3 activation pathway using homogeneous proteins of CED-4, CED-9 and EGL-1. One molecule of CED-9 binds to an asymmetric dimer of CED-4, but specifically recognizes only one of the two CED-4 molecules. This specific interaction prevents CED-4 from activating CED-3. EGL-1 binding induces pronounced conformational changes in CED-9 that result in the dissociation of the CED-4 dimer from CED-9. The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. Together, our studies provide important insights into the regulation of cell death activation in C. elegans. Sourec: Nature 437, 831-837 (6 October 2005) | doi: 10.1038/nature04002
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