Caspases were implicated in apoptosis with the discovery that CED-3, the product of a gene required for cell death in the nematode Caenorhabditis elegans, is related to mammalian interleukin-1b–converting enzyme (ICE or caspase-1). Caspases share similarities in amino acid sequence, structure, and substrate specificity. They are all expressed as proenzymes (30 to 50 kD) that contain three domains: an NH2-terminal domain, a large subunit (20 kD), and a small subunit (10 kD). Activation involves proteolytic processing between domains, followed by association of the large and small subunits to form a heterodimer.Caspases are among the most specific of proteases, with an unusual and absolute requirement for cleavage after aspartic acid. One role of caspases is to inactivate proteins that protect living cells from apoptosis. A clear example is the cleavage of ICAD/DFF45, an inhibitor of the nuclease responsible for DNA fragmentation, CAD (caspase-activated deoxyribonuclease).
ICAD is required for both the activity and inhibition of this nuclease, other negative regulators of apoptosis cleaved by caspases are Bcl-2 proteins. Caspases contribute to apoptosis through direct disassembly of cell structures, as illustrated by the destruction of nuclear lamina. Caspases also reorganize cell structures indirectly by cleaving several proteins involved in cytoskeleton regulation, including gelsolin, focal adhesion kinase (FAK), and p21-activated kinase 2 (PAK2). Death may be signaled by direct ligation of receptors at the cell surface, which leads to the activation of initiator caspases. These caspases then, directly or indirectly, activate the “executioner caspases”.Understanding how this signal can be recoupled to caspase activation may provide an opportunity to selectively kill transformed cells.


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