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Essential Role of CED-4 Oligomerization in CED-3 Activation and Apoptosis

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Science  28 Aug 1998:
Vol. 281, Issue 5381, pp. 1355-1357
DOI: 10.1126/science.281.5381.1355

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Abstract

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.

  • * Present address: Department of Molecular and Cellular Engineering and Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia, PA 19104, USA.

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