1. Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544, USA
2. Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA
3. Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea
4. Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA
5. Biology Department, Brookhaven National Laboratory, Upton, New York 11973, USA

Correspondence to: Yigong Shi¹ Correspondence and requests for materials should be addressed to Y.S. (Email: yshi@molbio.princeton.edu).

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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.