Ministry of Education Protein Science Laboratory, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
Cell. 2010 Apr 30;141(3):446-57. doi: 10.1016/j.cell.2010.03.017.
The CED-4 homo-oligomer or apoptosome is required for initiation of programmed cell death in Caenorhabditis elegans by facilitating autocatalytic activation of the CED-3 caspase zymogen. How the CED-4 apoptosome assembles and activates CED-3 remains enigmatic. Here we report the crystal structure of the complete CED-4 apoptosome and show that it consists of eight CED-4 molecules, organized as a tetramer of an asymmetric dimer via a previously unreported interface among AAA(+) ATPases. These eight CED-4 molecules form a funnel-shaped structure. The mature CED-3 protease is monomeric in solution and forms an active holoenzyme with the CED-4 apoptosome, within which the protease activity of CED-3 is markedly stimulated. Unexpectedly, the octameric CED-4 apoptosome appears to bind only two, not eight, molecules of mature CED-3. The structure of the CED-4 apoptosome reveals shared principles for the NB-ARC family of AAA(+) ATPases and suggests a mechanism for the activation of CED-3.
CED-4 同源寡聚物或凋亡体对于秀丽隐杆线虫程序性细胞死亡的起始是必需的，它通过促进 CED-3 半胱天冬酶原的自动催化激活来实现。CED-4 凋亡体如何组装并激活 CED-3 仍然是一个谜。在这里，我们报告了完整的 CED-4 凋亡体的晶体结构，并表明它由八个 CED-4 分子组成，通过以前未报道的 AAA(+)ATP 酶之间的接口组织成一个不对称二聚体的四聚体。这八个 CED-4 分子形成一个漏斗形结构。成熟的 CED-3 蛋白酶在溶液中是单体的，并与 CED-4 凋亡体形成一个活性全酶，在此全酶中，CED-3 的蛋白酶活性明显受到刺激。出乎意料的是，八聚体的 CED-4 凋亡体似乎只结合两个，而不是八个，成熟的 CED-3 分子。CED-4 凋亡体的结构揭示了 AAA(+)ATP 酶的 NB-ARC 家族的共同原则，并提出了 CED-3 激活的机制。
