InterPro domain: IPR035897

Toll proteins or Toll-like receptors (TLRs) and the interleukin-1 receptor (IL-1R) superfamily are both involved in innate antibacterial and antifungalimmunity 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 [ 1 ]. Interestingly, MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain [ 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 [Van der Biezen E.A., Jones J.D., Trends Biochem. Sci. 23:454-456(1998)].

Site directed mutagenesis and deletion analysis have shown that the TIR domain is essential for Toll and IL-1R activities. Sequence analysis have revealed the presence of three highly conserved regions among the different members of the 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 signalling, whereas box 3 is primarily involved in directing localization of receptor, perhaps through interactions with cytoskeletal element [ 5 ].

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 beta-sheet that is surrounded by a total of five helices on both sides, with connecting loop structures [ 6 ]. The loop regions appear to play an important role in mediating the specificity of protein-protein interactions [ 7 , 8 ].

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3. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612-5
4. Toll signaling pathways in the innate immune response. Curr. Opin. Immunol. 12, 13-9
5. Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J. Biol. Chem. 275, 4670-8
6. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111-5
7. NAD⁺ cleavage activity by animal and plant TIR domains in cell death pathways. Science 365, 793-799
8. TIR domains of plant immune receptors are NAD⁺-cleaving enzymes that promote cell death. Science 365, 799-803