SM00255

Toll - interleukin 1 - resistance

SMART entry
Member databaseSMART
SMART typedomain
Short nameTIR

Description
Imported from IPR000157

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
[8]
, 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+). In plants, TIR domains require self-association interfaces and a putative catalytic glutamic acid that is conserved in both bacterial TIR NAD+-cleaving enzymes (NADases) and the mammalian SARM1 (sterile alpha and TIR motif containing 1) NADase for cell death induction and NAD+ cleavage activity
[8, 10]
. 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 characterised in mammalian TIR domains involved in innate immunity, may be a more recent evolutionary adaptation
[11]
.

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 signalling 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
[5, 2, 3]
. Besides the mammalian and Drosophila proteins, a TIR domain is also found in a number of plant cytoplasmic proteins implicated in host defense
[9]
.

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
[4]
.

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, with connecting loop structures
[6]
. The loop regions appear to play an important role in mediating the specificity of protein-protein interactions
[7, 8]
.

References
Imported from IPR000157

1.TLR6: A novel member of an expanding toll-like receptor family. Takeuchi O, Kawai T, Sanjo H, Copeland NG, Gilbert DJ, Jenkins NA, Takeda K, Akira S. Gene 231, 59-65, (1999). View articlePMID: 10231569

2.IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Muzio M, Ni J, Feng P, Dixit VM. Science 278, 1612-5, (1997). View articlePMID: 9374458

3.Toll signaling pathways in the innate immune response. Anderson KV. Curr. Opin. Immunol. 12, 13-9, (2000). View articlePMID: 10679407

4.Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. Slack JL, Schooley K, Bonnert TP, Mitcham JL, Qwarnstrom EE, Sims JE, Dower SK. J. Biol. Chem. 275, 4670-8, (2000). View articlePMID: 10671496

5.T1/ST2 signaling establishes it as a member of an expanding interleukin-1 receptor family. Mitcham JL, Parnet P, Bonnert TP, Garka KE, Gerhart MJ, Slack JL, Gayle MA, Dower SK, Sims JE. J. Biol. Chem. 271, 5777-83, (1996). View articlePMID: 8621445

6.Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Xu Y, Tao X, Shen B, Horng T, Medzhitov R, Manley JL, Tong L. Nature 408, 111-5, (2000). View articlePMID: 11081518

7.NAD<sup>+</sup> cleavage activity by animal and plant TIR domains in cell death pathways. Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y, Chen J, Qi T, Gilley J, Lai JS, Rank MX, Casey LW, Gu W, Ericsson DJ, Foley G, Hughes RO, Bosanac T, von Itzstein M, Rathjen JP, Nanson JD, Boden M, Dry IB, Williams SJ, Staskawicz BJ, Coleman MP, Ve T, Dodds PN, Kobe B. Science 365, 793-799, (2019). PMID: 31439792

8.TIR domains of plant immune receptors are NAD<sup>+</sup>-cleaving enzymes that promote cell death. Wan L, Essuman K, Anderson RG, Sasaki Y, Monteiro F, Chung EH, Osborne Nishimura E, DiAntonio A, Milbrandt J, Dangl JL, Nishimura MT. Science 365, 799-803, (2019). PMID: 31439793

9.Plant disease-resistance proteins and the gene-for-gene concept. Van der Biezen EA, Jones JD. Trends Biochem. Sci. 23, 454-6, (1998). View articlePMID: 9868361

10.A phase transition enhances the catalytic activity of SARM1, an NAD<sup>+</sup> glycohydrolase involved in neurodegeneration. Loring HS, Czech VL, Icso JD, O'Connor L, Parelkar SS, Byrne AB, Thompson PR. Elife 10, (2021). PMID: 34184985

11.TIR Domain Proteins Are an Ancient Family of NAD<sup>+</sup>-Consuming Enzymes. Essuman K, Summers DW, Sasaki Y, Mao X, Yim AKY, DiAntonio A, Milbrandt J. Curr Biol 28, 421-430.e4, (2018). PMID: 29395922

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