Control of the activation of apoptosis is important both in development and in protection against cancer. In the classic genetic model Caenorhabditis elegans, the pro-apoptotic protein CED-4 activates the CED-3 caspase and is inhibited by the Bcl-2-like protein CED-9. Both processes are mediated by protein-protein interaction. Facilitating the proximity of CED-3 zymogen molecules was found to induce caspase activation and cell death. CED-4 protein oligomerized in cells and in vitro. This oligomerization induced CED-3 proximity and competed with CED-4:CED-9 interaction. Mutations that abolished CED-4 oligomerization inactivated its ability to activate CED-3. Thus, the mechanism of control is that CED-3 in CED-3:CED-4 complexes is activated by CED-4 oligomerization, which is inhibited by binding of CED-9 to CED-4.AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.FAU - Yang, XAU - Yang XFAU - Chang, H YAU - Chang HYFAU - Baltimore, DAU - Baltimore DLA - engID - CA51462/CA/NCIPT - Journal ArticleCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Biopolymers)RN - 0 (Calcium-Binding Proteins)RN - 0 (Ced-4 protein)RN - 0 (Ced-9 protein)RN - 0 (Cysteine Proteinase Inhibitors)RN - 0 (Enzyme Precursors)RN - 0 (Helminth Proteins)RN - 0 (Oligopeptides)RN - 0 (Proto-Oncogene Proteins)RN - 0 (Proto-Oncogene Proteins c-
bcl-2)RN - 0 (Recombinant Fusion Proteins)RN - 0 (bcl-x protein)RN - 109581-93-3 (Tacrolimus)RN - EC 3.4.22 (Cysteine Endopeptidases)RN - EC 3.4.22.- (Ced-3 protein)SB - IM