(Earnshaw et al., 1999). Caspases are divided into distinct subfamilies according to
their structural and sequence identities, and their substrate specificity is determined
by the specific pattern of four residues amino-terminal to the cleavage site (the P2-
P4 positions). While caspases typically function by inactivating proteins by
proteolytic cleavage, they can also, in some cases, activate the target by cleaving off a
negative regulatory domain. Caspase-mediated cleavage of key substrates underlies
many of the characteristic features of apoptosis such as nuclear shrinkage (Rao et al.,
1996; Buendia et al., 1999), plasma membrane blebbing (Rudel and Bokoch, 1997;
Coleman et al., 2001; Sebbagh et al., 2001), and internucleosomal DNA
fragmentation (Liu, X. et al., 1997; Enari et al., 1998; Sakahira et al., 1998).
Deficiency of specific caspases or their inhibition can prevent the induction of
Figure 1. Death and decoy receptors of the TNF receptor family.
Death receptors have variable numbers of cysteine-rich extracellular domains (CRDs) in their
extracellular ligand-binding amino terminal regions, and a homologous cytoplasmic sequence,
termed the ‘death domain’ (DD), which is essential for apoptosis signaling. Death receptors
are activated by ligands of the TNF gene superfamily; TNFR1 is ligated by TNFα, CD95/Fas
is bound by CD95L, DR3 interacts with Apo3L, and TRAIL-Rl and TRAIL-R2 are engaged
by Apo2L/TRAIL. DcR1 (TRAIL-R3) is structurally related to DR4 and DR5, but lacks a
cytoplasmic tail. DcR2 (TRAIL-R4) also resembles DR4 and DR5, but has a truncated
cytoplasmic DD. The extracellular domains of DcR1 and DcR2 compete with DR4 and DR5
for binding to Apo2L/TRAIL, but cannot initiate death signals in response to ligand-
engagement. DcR3 binds to CD95L and inhibits CD95-CD95L interactions.
DEATH RECEPTORS IN APOPTOSIS 3