Proteases, proteolysis, and apoptosis.
Proteolytic cleavage of a limited number of cellular proteins is a central biochemical feature of apoptosis. Aspartate-specific cysteine proteases, the so-called 'caspases', are the main enzymes involved in this process. At least ten homologues of interleukin-1 beta converting enzyme (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 ICE 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 substitution is observed in P2 and P3. Caspase activation might involve a proteolytic cascade similar to that of the coagulation cascade but the molecular ordering of these proteases in vivo remains to be established clearly. Calpains, serine proteases, granzymes and the proteasome-ubiquitin pathway of protein degradation are other proteolytic pathways that have been suggested to play a role in apoptosis. Substrate proteins can be either activated or degraded during cell death and the consequences of their cleavage remains mostly ill-understood. Nevertheless, the recent demonstration that protease inhibitors can rescue mice undergoing acute liver destruction indicates the accuracy of therapeutic strategies aiming to inhibit cell death-associated proteolysis.
Solary
E
E
Department of Biology and Therapy of Cancer, CJF INSERM 94-08, Faculty of Medicine, Dijon, France.
Eymin
B
B
Droin
N
N
Haugg
M
M
D000818:Animals; D017209:Apoptosis; D002154:Calpain / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011506:Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D011506:Proteins; D014452:Ubiquitins; D010450:Endopeptidases; D012697:Serine Endopeptidases; D002154:Calpain; D003546:Cysteine Endopeptidases