PROTEASES, PROTEOLYSIS, AND APOPTOSIS

Proteolytic cleavage of a limited number of cellular proteins is a cen tral biochemical feature of apoptosis. Aspartate-specific cysteine pro teases, the so-called 'caspases', are the main enzymes involved in thi s process. At least ten homologues of interleukin-1 beta converting en zyme (ICE), the first described human caspase, have been identified so far. The purified active proteins are heterodimers with a long and a short subunit derived from a common inactive precursor. Crystallized I CE has an original tetrameric, structure. The various caspases tend to show high degrees of homology around the active site Cys. Proteolysis by caspases minimally requires a tetrapeptide substrate in which Asp is an absolute requirement in P1 position, the P4 substrate residue is unique to each homologue, and much more widespread amino acid substit ution is observed in P2 and P3. Caspase activation might involve a pro teolytic cascade similar to that of the coagulation cascade but the mo lecular ordering of these proteases in vivo remains to be established clearly. Calpains, serine proteases, granzymes and the proteasome-ubiq uitin pathway of protein degradation are other proteolytic pathways th at have been suggested to play a role in apoptosis. Substrate proteins can be either activated or degraded during cell death and the consequ ences of their cleavage remains mostly ill-understood. Nevertheless, t he recent demonstration that protease inhibitors can rescue mice under going acute liver destruction indicates the accuracy of therapeutic st rategies aiming to inhibit cell death-associated proteolysis.