Genetics of Apoptosis

protein known to interact with TIR receptors. MyD88 is still considered the major
adapter in TIR signaling, as it seems to play a role in NF-κB signaling by both receptor
classes. Interestingly, MyD88 adapts the TIR/TIR-based interaction to one based on
death domains. While the C-terminal TIR domain binds to the receptor, the N-
terminal death domain apparently binds to the death domain of the interleukin-1
receptor-associated kinases (IRAKs). The four mammalian IRAKs are homologous
to the PELLE gene, which plays a role in TOLL-induced NF-κB activation in
Drosophila. In this well-studied model pathway, an additional deathdomain protein
called TUBE binds to the death domain of PELLE and plays an important role in
TOLL signaling. Mammals seem to lack a TUBE homolog, while a MyD88 homolog
has recently been described for Drosophila (Horng and Medzhitov, 2001).
The structure of the TIR domains of the TOLL-like receptors TLR2 and TLR3
have been described (Xu et al., 2000). The TIR domain contains a central five-
stranded parallel beta sheet, surrounded by five helices. It is thus very different from
the short, six-helix adapter proteins, although is serves a similar purpose and also
appears to favor trimerization. Currently, 22 mammalian proteins harboring a TIR
domain are known; they are listed in Table 7.

4.

Caspases and inhibitors

The main purpose of the death adapter proteins seems to be the signal-induced
oligomerization and subsequent activation of caspases by binding to their DED—or
CARD-containing prodomains. The fully active caspases are then able to cleave their
substrates, including other caspases. The death-inducing effect of an untimely
activated caspase can be very dangerous for an organism and a number of endogenous
inhibitors of caspase inhibitors exist for keeping these enzymes in check.

4.1

The caspase catalytic domain

The group of apoptotic proteases that was formerly called ‘ICE-like proteases’ is now
referred to as ‘caspases’, alluding to their properties as cysteine-proteases with a
cleavage specificity for an Asp-based motif (Earnshaw et al., 1999; Nicholson, 1999;
Grutter, 2000). The members of this protein family can be classified by at least two
different criteria: their mode of activation and their cleavage specificity. While the
former is a property encoded by the prodomain (DED, CARD, or neither), the
specificity is encoded in the catalytic domain. A typical caspase consists of three
different parts. The prodomain is removed after activation, while the remainder of
the protein is separated by a further activation cleavage into two subunits, p20 and
p10. The three-dimensional structures of several active caspases are available,
including those of caspase-1 (Walker et al., 1994; Wilson et al., 1994), caspase-3
(Rotonda et al., 1996), caspase-7 (Wei, Y. et al., 2000) and caspase-8 (Blanchard et
al., 1999; Watt et al., 1999). All of them were crystallized in the presence of a small

88 GENETICS OF APOPTOSIS