Genetics of Apoptosis

2.

The role of caspases in apoptosis

Sharad Kumar and Dimitrios Cakouros

1.

What are caspases?

As the name suggests, caspases (cysteinyl asgartate proteinases) are cysteine proteases
that cleave their substrates following an Asp residue. The prototypic member of the
caspase family is CED-3, a Caenorhabditis elegans protein essential for programmed
cell death during development (Chapter 10). Mutations in the ced-3 gene result in
the survival of 131 cells that normally die during development of the worm (Ellis and
Horvitz, 1986). Cloning of ced-3 indicated that its gene product is similar to a
mammalian cysteine protease termed interleukin-lβ-converting enzyme (now called
caspase-1) and a developmentally regulated protein Nedd2 (now called caspase-2)
(Yuan et al., 1993; Kumar et al. 1994; Wang et al., 1994). Subsequently, several
caspases have been cloned from various mammalian and nonmammalian species. A
total of 11 caspases have been described in man, 10 in mouse, four in chicken, four
in zebrafish, seven in Drosophila melanogaster, and three in C. elegans (reviewed in
Lamkanfi et al., 2002). Most work so far has been done with mammalian caspases,
although a significant body of information is now also available on Drosophila
caspases. Not all known caspases play a role in apoptosis, and caspase gene knockout
(k/o) in mice suggests that some caspases have tissue—and signal-specific functions
(reviewed in Colussi and Kumar, 1999; Zheng et al., 1999). This chapter focuses
mainly on caspases that play a role in cell death pathways.

2.

Types of caspases

Most living cells contain several caspases, and the inactive proteins exist constitutively
as unprocessed zymogen. Upon receiving an apoptotic signal, the proforms of caspases
undergo proteolytic processing to generate two subunits that comprise the active
enzyme. However, recent studies have shown that the cleavage of zymogen is not
always an obligatory requirement for caspase activation (see later). The structural
studies predict that the mature caspase is a heterotetramer, composed of two
heterodimers derived from two precursor molecules (reviewed in Shi, 2001). In