A cytochrome c-free fly apoptosome

The canonical caspase activation pathway, as first elucidated in the worm Caenorhabditis elegans, is largely conserved in metazoans. Recent structural and biochemical data demonstrate that in C. elegans, the caspase CED-3 is activated by a tetrameric CED-4 complex (apoptosome) that is prevented from assembling by interaction with the Bcl-2-like protein CED-9 until the BH-3-only protein EGL-1 sequesters CED-9 away.¹ CED-4 and its orthologues thus facilitate the activation of apical caspases (CED-3 and its orthologues) and provide a key regulatory step in the initial activation of caspases. The formation of the caspase-activating apoptosome in mammals is well documented^{2, 3, 4} and a recent publication from Christopher Akey's laboratory now reports the assembly and three-dimensional structure of a Drosophila apoptosome.⁵

In mammalian cells, the mitochondrial respiratory protein cytochrome c is released into the cytosol during apoptosis and assists the formation of an oligomeric Apaf-1 apoptosome.^{2, 3, 4, 6} Biochemical studies and the three dimensional structure of Apaf-1 apoptosome indicate that dATP is bound to the CED4 homology region and the binding of cytochrome c promotes Apaf-1 activation and the formation of an oligomer comprised of seven Apaf-1 molecules.^{2, 3, 4} In the final step, procaspase-9 is recruited to the active apoptosome by binding to the exposed Apaf-1 CARD. This apoptosome activates caspase-9, which can then activate downstream caspases (caspase-3 and -7) to execute cell death.^{2, 3, 4}

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