Structure of the CED-4–CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans

Nieng Yan, Jijie Chai, Eui Seung Lee, Lichuan Gu, Qun Liu, Jiaqing He, Jia-Wei Wu, David Kokel, Huilin Li, Quan Hao, Ding Xue and Yigong Shi ()
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Nieng Yan: Princeton University, Lewis Thomas Laboratory
Jijie Chai: Princeton University, Lewis Thomas Laboratory
Eui Seung Lee: University of Colorado
Lichuan Gu: Princeton University, Lewis Thomas Laboratory
Qun Liu: Cornell University
Jiaqing He: Brookhaven National Laboratory
Jia-Wei Wu: Princeton University, Lewis Thomas Laboratory
David Kokel: University of Colorado
Huilin Li: Brookhaven National Laboratory
Quan Hao: Cornell University
Ding Xue: University of Colorado
Yigong Shi: Princeton University, Lewis Thomas Laboratory

Nature, 2005, vol. 437, issue 7060, 831-837

Abstract: 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 Å 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.

Date: 2005
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DOI: 10.1038/nature04002

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