Genetics of Apoptosis

respects. It does not bind to a member of the TNF family but rather to the unrelated
nerve growth factor (NGF), and its role in neuronal apoptosis is still unclear. Even
more unusual is osteoprotegerin (OPG), the putative decoy receptor for RANKL/
TRANCE. This protein is secreted and contains the only known extracellular death
domains. Since the two death domains of OPG have no access to components of the
death-signaling pathway, OPG is clearly not a death receptor.

3.

Adapter domains

The binding of the death receptors to their ligands induces the assembly of a number
of adapter proteins at the cytoplasmic face of the receptor. The resulting multiprotein
complex is sometimes referred to as ‘DISC’ (death-inducing signalingcomplex). The
recruitment of the adapter proteins is mediated by a number of specialized interactions
domains of the DD, DED, and CARD class, which share a common six-helix bundle
fold (Fesik, 2000) and are also distantly related by sequence (Hofmann et al., 1997).

3.1

The death domain (DD)

The death domain was originally defined as a region of sequence similarity in the
cytoplasmic moieties of the two archetypal death receptors Fas and TNF-R1 (Itoh
and Nagata, 1993; Tartaglia et al., 1993). Clues to the function of this homology
domain came from experiments showing that the death domain of both receptors is
the site of interaction with their downstream targets. Mutagenesis experiments
demonstrated the importance of an intact death domain for apoptosis induction,
while the membrane-proximal part of the intracellular domain was less important
(Itoh and Nagata, 1993; Tartaglia et al., 1993). A missense mutation within the death
domain of Fas is the cause of the lymphoproliferative disease phenotype observed in
lpr mice (Watanabe-Fukunaga et al., 1992).
Initially, three proteins (FADD, TRADD, and RIP) were found to interact with
the receptor death domains (Boldin et al., 1995; Chinnaiyan et al., 1995; Hsu et al.,
1995; Stanger et al., 1995). Interestingly, in all three interactors a region with
homology to the death domain was identified, which also coincided with the region
mediating the receptor interaction. This was a clear indication that death domains
function by mediating a heterodimerization with other death domains.
The death domains of Fas, TNF-R1, FADD, TRADD, and RIP form a
heterogeneous family with moderate but readily detectable sequence similarity in the
order of 20–30% residue identity. Due to the importance of DD-DD
heterodimerization as the first step of intracellular death receptor signaling, several
groups have employed bioinformatic methods to screen sequence databases for new
death-domain proteins, with the rationale that those proteins might constitute either
additional death receptors or new adapter proteins. In two initial screens, several
known proteins were found to contain regions related to the death domain, including

78 GENETICS OF APOPTOSIS