3.5
The Toll/IL-1R domain (TIR)The TIR domain can with some justification be grouped with the death adapter
domains, although it is neither related to the six-helix domain family nor does it
strictly signal apoptosis. Despite these differences, there are also a number of common
features. The name TIR stems from the identification of the domain as a homology
region in the cytoplasmic portions of TOLL and IL-1 receptors. The TIR domain
plays a crucial role in the signaling by these two receptor families, in a manner
analogous to that of the death domain in death receptor signaling. Members of the
IL-1 receptor family respond to the binding of interleukin-1 (both a and β) as well
as interleukin-18. Several members of this receptor family are orphans in the sense
that their ligands have not yet been identified. Members of the TOLL family, often
called TLR (‘TOLL-like receptors’), recognize factors indicating a bacterial or fungal
infection, among them lipopolysaccharides and related polymers. The different ligand
preferences are reflected in fundamentally different ligand-binding domains. While
the interleukin-1 receptor family has Ig-type modules in their ectodomain, TOLL
and the TLRs have leucine-rich repeats (LRRs) instead. Both receptor classes elicit
similar intracellular responses, with NF-κB activation being the most intensively
studied effect. This common aspect of signal transduction is mediated by the TIR
domain, which is common to both receptor classes (O’Neill, 2000; Schnare et al.,
2001).
Like the death domain, the TIR domain apparently works by recruiting a TIR-
containing adapter protein to the receptor. Until the recent discovery of the Mal
protein (Fitzgerald et al., 2001), the MyD88 gene product was the only adapter
Table 6 Mammalian pyrin domain proteins
Domain abbreviations: PYD, pyrin domain; BBOX, B-box type Zn-finger; NACHT, ATPase
domain; IFI-CT, C-terminal domain in interferon-induced proteins.
FUNCTIONAL DOMAINS IN APOPTOSIS PROTEINS 87