Genetics of Apoptosis

viruses encoding these proteins belong to two different classes: most of them are γ-
herpesviruses, while the poxvirus MCV (molluscum contagiosum virus) encodes two
of the short double-DED proteins (Thome et al., 1997). The viral proteins were of
particular interest in the light of the preceding discovery of caspase-8, with which
they share the tandem DEDs and considerable sequence relationship. Several
independent studies provided evidence that the viral proteins were able to inhibit
FADD mediated apoptosis by binding to the death effector domains of FADD and/
or caspase-8 (FLICE), and thus disrupting their interaction (Bertin et al., 1997; Hu
et al., 1997; Thome et al., 1997). This class of viral proteins was termed v-FLIPs, for
viral FLICE inhibitory proteins. Subsequently, a cellular homolog of the v-FLIPs was
identified and named c-FLIP, or, alternatively, CASH, MRIT, CLARP, CASPER, I-
FLICE, or usurpin (Goltsev et al., 1997; Han et al., 1997; Inohara et al., 1997; Irmler
et al., 1997; Rasper et al., 1998). The c-FLIP gene produces several alternative splice
forms. A short form corresponds directly to the viral FLIP proteins, while a long splice
form generates a protein with high similarity to caspase-8, albeit with an inactive
protease domain. This long form of FLIP is a particularly good inhibitor of caspase-8
since it interacts with the enzyme both via its death effector domains and via the
caspase-like domain.
Despite several attempts, no additional death effector domain proteins have been
identified since then, making the DED family relatively small by comparison (see
Table 4). Like the death domain, the death effector domain spans approximately 90
residues. Some representative DEDs are aligned in Figure 1. The three-dimensional
NMR structure of the FADD death effector domain shows a fold related to that of
the death domain (Eberstadt et al., 1998), confirming an earlier prediction derived
from subtle sequence similarities (Hofmann et al., 1997). The ordered part of the
NMR structure corresponds well with the domain boundaries predicted from
sequence analysis. This was to be expected, since the tandem arrangement of DEDs
in the very short viral FLIP proteins had allowed for a precise delineation of the
homology domain. At present, no structures for DED-DED complexes are known,

Table 4 Death effector domain proteins

Domain abbreviations: DD, death domain; DED, death effector domain.

82 GENETICS OF APOPTOSIS