The typical death domain spans a region of approximately 90 residues with pairwise
similarities between selected members being as low as 15%. An alignment of selected
death domains is shown in Figure 1. Several three-dimensional structures of death
domains have been reported, including those of Fas (Huang et al., 1996), NGF-R
(Liepinsh et al., 1997), and FADD (Jeong et al., 1999). All structures show a highly
similar fold consisting of six antiparallel α-helices, forming a compact bundle. The
N- and C-termini of the domain are in close vicinity, a property that allows the DD
to be inserted into a heterologous sequence with minimal structural disruption, a
hallmark of truly modular domains. The domain boundaries derived from the DD
structures are in good agreement with the boundaries of the observed sequence
homology. Of particular interest is the recently solved structure of a complex between
the death domains of the Drosophila proteins TUBE and PELLE (Xiao et al., 1999).
Figure 1. Alignment of representative members of the DD, DED, CARD and
PYD families.
Residues identical or conserved in more than 50% of all sequences are shown by
black and gray shadings, respectively. The lines above the DD, DED, and CARD
alignment indicate the α-helices derived from the respective domain structures.
The lines above the PYD alignment indicate predicted α-helices.The interaction surface seen in this complex is probably not the only one being used
for DD-DD interactions. There is evidence that, at least in apoptosis signaling, death
domains are able to form heterotrimers, an architecture that requires two different
DD-DD interaction surfaces. The problem of the interaction surface for death
domains and the related domain families of the six-helix class is the topic of a recent
review (Weber and Vincenz, 200 la).
Functionally, all studied death domains appear to mediate interactions of unclear
stoichiometry with other death-domain proteins. DD-DD interactions have a strong
preference for apoptosis signaling pathways but they also appear to play a role outside
apoptosis. The NF-kB activation pathway, which also shares other features with
apoptotic signaling, makes heavy use of death domains, too. This is true for the
80 GENETICS OF APOPTOSIS