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

Nature. 2005 Oct 6;437(7060):831-7. 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 A 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Binding Sites
  • Caenorhabditis elegans / chemistry*
  • Caenorhabditis elegans / cytology*
  • Caenorhabditis elegans Proteins / chemistry*
  • Caenorhabditis elegans Proteins / metabolism*
  • Calcium-Binding Proteins / chemistry*
  • Calcium-Binding Proteins / metabolism*
  • Caspases / metabolism
  • Enzyme Activation
  • Models, Molecular
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Protein Binding
  • Protein Structure, Quaternary
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2
  • Repressor Proteins / chemistry
  • Repressor Proteins / metabolism
  • Substrate Specificity


  • Apoptosis Regulatory Proteins
  • Caenorhabditis elegans Proteins
  • Calcium-Binding Proteins
  • Ced-4 protein, C elegans
  • Ced-9 protein, C elegans
  • EGL-1 protein, C elegans
  • Multiprotein Complexes
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Repressor Proteins
  • Adenosine Triphosphate
  • Caspases
  • ced-3 protein, C elegans

Associated data

  • PDB/2A5Y