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

• Published in: Nature 2005-10, Vol.437 (7060), p.831-837
• Main Authors: Yan, Nieng, Hao, Quan, Lee, Eui Seung, Wu, Jia-Wei, Gu, Lichuan, Li, Huilin, Liu, Qun, Chai, Jijie, Kokel, David, Xue, Ding, Shi, Yigong, He, Jiaqing
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Ageing, cell death; Animals; Apoptosis; Apoptosis Regulatory Proteins; Binding Sites; Biochemistry; Biological and medical sciences; Caenorhabditis elegans - chemistry; Caenorhabditis elegans - cytology; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - metabolism; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - metabolism; Caspases - metabolism; Cell death; CELL KILLING; Cell physiology; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DEATH; DIMERS; DISSOCIATION; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Genes; Genetic markers; Humanities and Social Sciences; MATERIALS SCIENCE; Models, Molecular; Molecular and cellular biology; Molecular biology; Mortality; multidisciplinary; Multiprotein Complexes - chemistry; Multiprotein Complexes - metabolism; national synchrotron light source; NEMATODES; Proteases; Protein Binding; Protein Structure, Quaternary; PROTEINS; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2; REGULATIONS; Repressor Proteins - chemistry; Repressor Proteins - metabolism; RESOLUTION; Science; Science (multidisciplinary); Substrate Specificity
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature04002

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 .