molecule inhibitor. According to the structure, an activated caspase consists of two
p20/p10 heterodimers. In the structure, the C-terminus of the p20 subunit is far
away from the N-terminus of the corresponding p10 subunit, but close to the N-
terminus of the other p10 subunit. This arrangement either requires a large
conformational change upon activation or, more likely, indicates an exchange of
subunits (Fesik, 2000). Other information that can be obtained from the caspase
structures includes a general idea of the reaction mechanism and an explanation for
the preferred cleavage after aspartate residues. The caspases differ from most other
proteases family in the recognition of a complex cleavage signal. While the receptor-
proximal caspases, or ‘initiator caspases’, prefer the motif [LV]ExD, the downstream
caspases, or ‘executor caspases’, prefer DExD instead. This difference in specificity
can also be explained by properties of the respective x-ray structures.
Recently, the relationship between caspases and several other protease families was
established by sequence analysis (Uren et al., 2000). The members of the newly
identified families are cysteine proteases as well and cleave after an aspartate residue.
By definition, those proteins should also be considered caspases. A major difference
between the classical caspases and the new ‘paracaspases’ and ‘metacas pases’ is the
lack of a p10-like sequence in the latter families. The paracaspases include the death-
domain-containing MLT gene, while the metacaspases are more ancient and even
Table 7 Mammalian Toll/IL-1R domain proteins
Domain abbreviations: Ig, immunoglobulin domain; TM, transmembrane region; TIR,
TOLL/IL-1R domain; DD, death domain; Arm, armadillo-repeats; SAM, sterila alpha module.
FUNCTIONAL DOMAINS IN APOPTOSIS PROTEINS 89