Genetics of Apoptosis

example, mammalian caspase-2, and Drosophila DRONC and DAMM prefer a
minimum of five residues in the substrates, and tetrapeptide substrates are poorly
cleaved by these caspases (Talanian et al., 1997a; Dorstyn et al. 1999a; Hawkins et
al., 2000; Harvey et al., 2001). By the P4-P2 specificities, the mammalian caspases
have been divided into three groups (Thornberry et al., 1997). The group I caspases
(caspase-1, -4, and -5) prefer a hydrophobic residue in the P4 position, group II
caspases (caspase-2, -3, and -7) have a strict requirement for an Asp in the P4 position,
and group III caspases (caspase-6, -8, -9, and -10) prefer a branched chain aliphatic
amino acid in P4 (Table 1). Group II caspases, caspase-3 and -7 in particular, with a
P4-P1 specificity of DxxD are considered to be activated by upstream initiator
caspases such as caspase-8 and caspase-9. The preferred P3 residue for most
mammalian caspases is Glu (Thornberry et al., 1997). Although all caspases require
an Asp in the P1 position, Drosophila DRONC has been shown to possess some
cleavage activity on peptide substrates carrying Glu in P1 (Hawkins et al., 2000).
DRONC also shows a strong preference for Thr, Ile, or Val at P2 (Hawkins et al.,
2000). The Drosophila effector caspases DCP-1, DRICE, and DECAY share a
substrate specificity identical to that of mammalian group II caspases (Fraser and
Evan, 1997; Dorstyn et al., 1999b; Song et al., 2000).

5.

Caspase activation

As mentioned above, specific adaptor molecules, via protein-protein interaction
domains, mediate the recruitment of procaspase molecules to the death-signaling
complexes. Among the three types of domains mediating interactions between
molecules of the death effector apparatus, death domains (DDs) are found in
upstream components of the apoptotic pathways, such as death receptors (e.g., CD95,

Table 1. Substrate specificities of various mammalian caspasesa

aP4-P1 residues are shown (except for caspase-2 substrate VDVAD). In all cases, caspase-
mediated cleavage occurs following the Asp residue in P1 position. See text for details and
references.

36 GENETICS OF APOPTOSIS