InterPro domain: IPR000157

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 ].

This entry represents the Toll/interleukin-1 receptor (TIR) domain, which is the conserved cytoplasmic domain of approximately 200 amino acids, found in Toll-like receptors (TLRs) and their adaptors. Proteins containing this domain can also be found in plants, where they mediate disease resistance, and in bacteria, where they have been associated with virulence. Interestingly, the TIR domains from proteins present in all three major domains of life have been shown to cleave nicotinamide adenine dinucleotide (NAD+). It has been suggested that the primordial function of the TIR domain is the enzymatic cleavage of NAD+ and that the scaffolding function, which is best characterized in mammalian TIR domains involved in innate immunity, may be a more recent evolutionary adaptation [ 9 ].

1. TLR6: A novel member of an expanding toll-like receptor family. Gene 231, 59-65
2. T1/ST2 signaling establishes it as a member of an expanding interleukin-1 receptor family. J. Biol. Chem. 271, 5777-83
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
9. TIR Domain Proteins Are an Ancient Family of NAD⁺-Consuming Enzymes. Curr Biol 28, 421-430.e4