施一公2014-04-14 4:11 PM

CED-4/CED-9复杂物结构提供了对秀丽隐杆线虫程序性细胞死亡的深入了解 Structure of the CED-4/CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans

论文摘要
EGL-1 ,CED-9,CED-4和CED-3四个基因间的相互作用控制着秀丽隐杆线虫程序性细胞死亡的启动。细胞杀伤蛋白酶CED-3的活化需要CED-4。然而CED–4受CED-9组成性抑制直到它通过EGL-1得到释放。在此我们展示了2.6分辨率下CED-4-CED-9复合物的晶体结构以及利用CED-4,CED-9和EGL-1的均质蛋白质进行CED-3活化途径的完整重构。CED-9中的某个分子与CED-4的不对称二聚体相结合,但只能特定识别这两个CED-4分子的其中之一。这种特定互动避免了CED-4对 CED-3的激活。EGL-1的结合诱导了CED- 9明显的构象变化,该结果导致了CED-4二聚体从CED-9的解离。被释放的CED-4二聚体进一步二聚化以形成四聚体,这有利于CED-3的自身活化。总之我们的研究为秀丽隐杆线虫细胞死亡活化的调节提供了重要见解。
Abstract
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 A 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.

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