caspases activate

Aside from the ligation of death receptors there are a number of other mechanisms through which the caspase cascade can be activated. Granzyme B can be delivered into cells by cytotoxic T lymphocytes and is able to directly activate caspases 3, 7, 8 and 10. The mitochondria are also key regulators of the caspase cascade and apoptosis. Release of cytochrome C from mitochondria can lead to the activation of caspase 9, and then of caspase 3. This effect is mediated through the formation of an apoptosome, a multi-protein complex consisting of cytochrome C, Apaf-1, pro-caspase 9 and ATP. The formation of the apoptosome is illustrated below.

Cytochrome C released from the mitochondria binds to the cytosolic protein Apaf-1. This interaction results in a conformational change in Apaf-1 which, when stabilised by the binding of ATP, allows molecules of Apaf-1 to associate with each other. This results in the formation of a wheel-like structure that contains 7 molecules each of Apaf-1, cytochrome C and ATP. This wheel-like structure, known as the apoptosome, permits the recruitment of 7 molecules of procaspase-9 to the complex. The exact mechanism of caspase activation is still uncertain although two possibilities have been proposed. In one case the Apaf-1, cytochrome C and procaspase-9 complex can act as a stage to activate cytosolic procaspase-9 as it is recruited to the apoptosome. In the other scenario two apoptosome have been proposed to interact with each other and to activate the caspase-9 located on the other apoptosome