2:1 Stoichiometry of the CED-4-CED-9 complex and the tetrameric CED-4: insights into the regulation of CED-3 activation

Cell Cycle. 2006 Jan;5(1):31-4. doi: 10.4161/cc.5.1.2263. Epub 2006 Jan 18.


Four evolutionally conserved proteins -EGL-1, CED-9, CED-4 and CED-3- collectively control the initiation of programmed cell death (PCD) in Caenorhabditis elegans. Activation of CED-3, the cell killing caspase, requires CED-4. The pro-death function of CED-4 is inhibited by the mitochondria-bound CED-9. Crystal structure of the 150-kDa CED-4-CED-9 complex at 2.6 A resolution reveals a 2:1 stoichiometry between CED-4 and CED-9. EGL-1 binding to CED-9 results in the dissociation of CED-4 from the CED-4-CED-9 complex. The freed CED-4 dimer further dimerizes to form a tetramer. Only the CED-4 tetramer, but not dimer or monomer, is capable of activating CED-3. Thus, CED-9 inhibits CED-4-mediated activation of CED-3 by sequestering CED-4 dimer from further dimerization. On the basis of structural and biochemical analyses, working models are proposed to explain the mechanism by which CED-4 facilitates CED-3 activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Caenorhabditis elegans / chemistry*
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Caspases / chemistry
  • Caspases / genetics
  • Caspases / metabolism*
  • Enzyme Activation
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2


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