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

Nieng Yan, Jijie Chai, Seung Lee Eui, Lichuan Gu, Qun Liu, Jiaqing He, Jia Wei Wu, David Kokel, Huilin Li, Quan Hao, Ding Xue, Yigong Shi

Research output: Contribution to journalArticle

163 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)831-837
Number of pages7
JournalNature
Volume437
Issue number7060
DOIs
StatePublished - Oct 6 2005

All Science Journal Classification (ASJC) codes

  • General

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