ESSENTIAL ROLE OF CED-4 OLIGOMERIZATION IN CED-3 ACTIVATION AND APOPTOSIS

Control,of the activation of apoptosis is important both in developmen t and in protection against cancer. In the classic genetic model Caeno rhabditis elegans,;the pro-apoptotic protein CED-4 activates the CED-3 caspase and is inhibited by the Bcl-2-like protein CED-9, Both proces ses are mediated by protein-protein interaction. Facilitating the prox imity of CED-3 zymogen molecules was found to induce caspase activatio n and cell death. CED-4 protein oligomerized in cells and in vitro. Th is oligomerization induced CED-3 proximity and competed with CED-4:CED -9 interaction. Mutations that abolished CED-4 oligomerization inactiv ated 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 oligomerizat ion, which is inhibited by binding of CED-9 to CED-4.