Toll proteins or Toll-like receptors (TLRs) and the interleukin-1 receptor
(IL-1R) superfamily are both involved in innate antibacterial and antifungal
immunity in insects as well as in mammals. These receptors share a conserved
cytoplasmic domain of approximately 200 amino acids, known as the Toll/IL-1R
homologous region (TIR). The similarity between TLRs and IL-1Rs is not
restricted to sequence homology since these proteins also share a similar
signaling pathway. They both induce the activation of a Rel type transcription
factor via an adaptor protein and a protein kinase . Interestingly, MyD88,
a cytoplasmic adaptor protein found in mammals, contains a TIR domain
associated to a DEATH domain (see <PDOC50017>) [2,3,4]. Besides the mammalian
and Drosophila proteins, a TIR domain is also found in a number of plant
cytoplasmic proteins implicated in host defense .
Site directed mutagenesis and deletion analysis have shown that the TIR domain
is essential for Toll and IL-1R activities. A principal function of TIR
domains is thought to be to mediate homotypic protein-protein interactions in
the signal transduction process . Sequence analyses have revealed the
presence of three highly conserved regions among the different members of the
TIR family: box 1 (FDAFISY), box 2 (GYKLC-RD-PG), and box 3 (a conserved W
surrounded by basic residues). It has been proposed that boxes 1 and 2 are
involved in the binding of proteins involved in signaling, whereas box 3 is
primarily involved in directing localization of receptor, perhaps through
interactions with cytoskeletal elements .
Resolution of the crystal structures of the TIR domains of human Toll-like
receptors 1 and 2 has shown that they contain a central five-stranded parallel
β-sheet that is surrounded by a total of five helices on both sides .
Some proteins known to contain a TIR domain are listed below:
Mammalian interleukin-1 receptor. It is composed of two type I integral
membrane proteins, IL-1R and IL-1RacP, that share three Ig domains
(extracellular) and one TIR domain (cytoplasmic) .
Myeloid differentiation factor (MyD88), a cytoplasmic protein found in
mammals. It also contains a DEATH domain and acts as an adaptor protein in
IL-1R and TLR mediated signaling [2,3,4].
Toll, from Drosophila. The Toll signaling pathway is required for the
establishment of the dorso-ventral axis during embryogenesis and plays an
important role in the immune response against bacteria and fungi. Toll
contains two extracellular LRRs, adjacent cysteine containing motifs, one
transmembrane domain, an intracellular TIR domain and an intracellular
inhibitory domain .
LRR and TIR domains containing proteins from plants. These cytoplasmic
proteins are important in the host response to infection .
We developed a profile that covers the entire TIR domain.
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