TNFR1, DR3, DR4, and DR5) and the adaptor molecules that are recruited to these
receptors (e.g., FADD and TRADD) (reviewed in Ashkenazi and Dixit, 1998).
However, DEDs and CARDs are generally responsible for recruiting class I caspase
precursors to death effector complexes through specific adaptor molecules (Table 2).
DD-mediated association of receptors and adaptors usually occurs as a consequence
of ligand-dependent activation of death receptors. NMR structures of the DD, DED,
and CARD show that the three domains share a very similar structure consisting of
six or seven antiparallel, amphipathic α-helices (Huang et al., 1996; Eberstadt et al.,
1998; Chou et al., 1998; Qin et al., 1999).
5.1
Caspase activation by oligomerizationVarious studies have shown that procaspase oligomerization can induce caspase
activation (reviewed in Kumar, 1999; Kumar and Colussi, 1999). Both initiator
caspases, such as CED-3, and caspase-8 and -9, and effector caspases, such as
caspase-3, can undergo proteolytic processing when induced to oligomerize by
artificial means (Butt et al., 1998; Colussi et al., 1998b; MacCorkle et al., 1998;
Martin et al., 1998; Muzio et al., 1998; Yang et al., 1998a). On the basis of these
studies, the events leading to the activation of initiator caspases were proposed to
involve the following steps: first, conformational changes due to upstream signaling
events result in the recruitment of adaptor molecules to a death complex; second, this
is followed by further changes that promote the recruitment of caspases through
specific domains; and, finally, close proximity of procaspase molecules allows inter-
or intramolecular catalysis and activation of the zymogen. The exact mechanism of
processing of caspase zymogen is not fully understood, but zymogen forms of initiator
caspases are predicted to contain low-level protease activity that mediates their
autoactivation (reviewed in Stennicke and Savesen, 1999).
Table 2. Adaptors for various apoptotic initiator caspases and the domains that mediate caspase/
adaptor interactions
THE ROLE OF CASPASES IN APOPTOSIS 37