‘developmental’ pathway in flies, where the TOLL receptor signals via the DD
proteins TUBE and PELLE, as well as for the ‘immunologic’ pathway in mammals,
where IL-1 receptor and TOLL-like receptors (TLRs) signal via the IRAK kinases
and MyD88 (O’Neill and Greene, 1998). In addition, there are several orphan DD
proteins with no recognizable link to either apoptosis or TOLL/IL1R signaling. In
these cases, which include ankyrin and the unc-5 type receptors, the interaction
partners and function of the death domains are not known.
3.2
The death effector domain (DED)The ‘death effector domain’ (DED) was originally defined in a purely functional
sense as the N-terminal region of the death adapter protein FADD, without any
reference to sequence homology. Overexpression of FADD leads to the induction of
apoptosis in cell lines. When the N- and C-terminal halves of FADD were
overexpressed separately, only the former was capable of inducing apoptosis. As a
consequence, a model of FADD function was derived in which FADD couples to
the receptor by its C-terminal death domain and induces cellular death by its N-
terminal half (Boldin et al., 1995; Chinnaiyan et al., 1995; 1996b). By contrast, the
death-inducing property of the TNF-receptor associated protein TRADD is not
caused by a death effector domain in that protein but rather by a secondary interaction
between TRADD and the DED-containing FADD (Varfolomeev et al., 1996).
The important role of the death effector domain of FADD prompted a search for
interaction partners, the rationale being that those proteins would most likely
constitute the adjacent downstream component of death signaling. In parallel,
bioinformatic screens were used to search for additional proteins harboring regions
with similarity to the DED. Those proteins would be candidates for additional death
effectors, maybe working in the context of other death receptors. The experimental
approach was faster and yielded results that fitted both bills: By using a yeast two-
hybrid screen, a DED-interacting protein with a very interesting domain structure
was identified (Boldin et al., 1996; Muzio et al., 1996). The identified protein,
originally called Mach or FLICE, is now known as caspase-8. It was immediately
clear that caspase-8 was a component of apoptosis signaling, since related caspases,
particularly caspase-3, were already known to have a central role in this process
(Cohen, 1997; Salvesen and Dixit, 1997). Interestingly, the N-terminus of caspase-8
carried two copies of a tandem repeat, a strong resemblance to the death effector
domain of FADD. This finding established the death effector domain also as a
homology domain. The fact that this region was identified as the active FADD
interactor suggested that the death effector domain is able to mediate the interaction
with other death effector domains, in a manner similar to that of the death domain.
The bioinformatic searches yielded a small number of additional proteins
containing the DED homology domain. Besides the astrocytic phosphoprotein
PEA-15, a number of small viral proteins were identified, all of them containing two
copies of the death effector domain in tandem arrangment (Thome et al., 1997). The
FUNCTIONAL DOMAINS IN APOPTOSIS PROTEINS 81