Artificial death switches: induction of apoptosis by chemically induced caspase multimerization.

Abstract

Apoptosis involves the activation of an unusual class of cysteine proteases, termed caspases (for cysteine aspartic acid-specific protease) (5, 6). The original evidence for an involvement of caspases in apoptosis came from genetic analyses of programmed cell death in the nematode C. elegans: loss-of-function mutations in ced-3, which encodes a caspase, lack programmed cell death during development (7, 8). A large number of mammalian caspases have been isolated in recent years, and evidence for their involvement in apoptosis has come from a variety of inhibition and overexpression studies (5). Caspases are synthesized as inactive zymogens that need to be proteolytically processed to generate the active enzyme (6). Based on the known three-dimensional structure of two caspases (caspase-1 and -3), it is thought that the active protease consists of two heterodimers that are produced by internal proteolytic cleavages of the pro-enzyme. This leads to the removal of an N-terminal prodomain and the generation of a large (p20) and small (p10) subunit. Significantly, these cleavages occur after aspartate residues at substrate recognition consensus sites for caspases, and mature caspases can often cleave and activate their own as well as other caspase zymogens in vitro. This has led to the idea of a …