2.1
The TNF familyTwo excellent reviews covering all aspects of the TNF and TNFR families have
appeared recently (Locksley et al., 2001; Bodmer et al., 2002); they contain a far more
detailed discussion of death-ligand and -receptor biology than can be provided here.
Currently, the mammalian TNF family comprises 18 members, of which at least
three are known to induce cell death upon binding to their cognate receptors
(Table 2). The other ligands have roles in inflammation or cell differentiation; some
of them are able to modulate or even inhibit cell death via induction of the NF-κB
pathway. With one exception, all of the TNF ligands are type II transmembrane
proteins; that is, their N-terminus is localized inside the cell while their C-terminus
faces the outside. VEGI (vascular endothelial growth inhibitor) is a secreted protein.
Several of the other ligands are also found in secreted forms, a fact which can be
attributed either to alternative splicing or to proteolytic shedding of the ectodomain.
In particular, the latter phenomenon is frequently observed, although the outcome
depends on the ligand involved; while the soluble of FasL form is almost inactive
(Tanaka et al., 1998), ectodomain shedding appears to be required for activity of the
EDA (ectodysplasin A) ligand (Chen et al., 2001).
A defining feature of all members of the TNF family is the presence of a domain,
sometimes referred to as the ‘TNF homology domain’ or THD. The THD is
invariably localized at the extreme C-terminus, which in type II transmembrane
proteins corresponds to the distal end of the ectodomain. In some of the smaller
proteins, such as lymphotoxin-α or OX-40L, the ectodomain consists exclusively of
the THD. Some of the larger proteins, in particular TRAIL and EDA, contain an
extended ‘stalk region’ between the membrane and the THD. The active form of all
ligands belonging to the TNF family is a trimer. The prevalence for trimerization is
a property of the THD domain, as can be seen from the available three-dimensional
structures of the ligands TNF (Jones et al., 1989), lymphotoxin-α (Banner et al.,
1993), CD40L (Karpusas et al., 1995), and TRAIL (Cha et al., 2000).
The average THD region spans 150 residues and adopts a β-sandwich structure
consisting of two layers of five β-strands each. Interestingly, the three-dimensional
fold of the THD domain resembles that of the Clq domain found in proteins of the
complement system (Shapiro and Scherer, 1998). There are reasons to assume that
this relationship is biologically meaningful, since the Clq domain is able to form
trimers like members of the TNF family. Moreover, the similarity between the two
domain families is not restricted to the structure but can also be detected by sequence
profile methods, a fact which normally indicates descent from a common ancestral
domain. It is not unreasonable to speculate that some Clq-like domains might bind
to receptors resembling members of the TNFR family. For another structural
similarity of the THD, that to capsid proteins of small spherical plant viruses, the
biologic relevance it not clear. The viral proteins form pentamers rather than timers,
and a sequence relationship could not be established.
FUNCTIONAL DOMAINS IN APOPTOSIS PROTEINS 75