Genetics of Apoptosis

then deposited in one of the existing domain databases, which can be used to analyze
newly identified sequences for their domain content (Hofmann, 1998; Attwood,
2000). Several competing domain and motif databases exist, including PROSITE,
PFAM, and SMART, which contain descriptors for most if not all of the known
domains involved in apoptosis signaling (Schultz et al., 1998; Hofmann et al., 1999;
Bateman et al., 2000). Recently, a new meta-database named INTERPRO has been
established; it tries to combine the descriptors of several domain databases under a
single user interface (Apweiler et al., 2001). Pointers to the very useful search engines
of the domain databases are provided in Table 1.

1.3

Functional domains in apoptosis

Many of the ‘classical’ signal transduction processes use a relatively straight path from
receptor binding to the activation of corresponding transcription factors.
Components found in many of those pathways include small GTPases, their regulator
and effector proteins, kinases or even kinase cascades, and eventually transcription
factors. By contrast, the signaling pathway leading to cell death follows a different
paradigm. Here, most of the usual classes of signaling protein are avoided, and several
layers of specific adapter proteins, together with a proteolytic caspase cascade, are
used instead. The adapter proteins follow a specific domain-based interaction code,
which is outlined in Section 6.
Interestingly, most of the domains occurring in the apoptosis adapters and active
components are found exclusively in this pathway. Thus, a new protein found to
contain one of the apoptosis-specific domains can be considered a new component
in apoptotic signaling, or at least a very good candidate for this function.
Consequently, the mining of sequence databases for new proteins containing
apoptosis-specific domains has been a rich source of new apoptosis regulators.

2.

Death ligands and receptors

The first step in the induction of receptor-mediated apoptosis is the binding of a
trimeric ‘death ligand’ to a cognate ‘death receptor’. The known death ligands are all
members of a protein family named after its founding member, the tumor necrosis
factor TNF. The receptors for proteins of the TNF family also belong to a single
family that includes all known death receptors.

Table 1 Search engines of domain and motif databases

74 GENETICS OF APOPTOSIS