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PROSITE documentation PDOC50104 [for PROSITE entry PS50104]

TIR domain profile


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 [1]. 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 [5].

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 [6]. 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 [7].

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 [8].

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) [7].
  • 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 [4].
  • LRR and TIR domains containing proteins from plants. These cytoplasmic proteins are important in the host response to infection [5].

We developed a profile that covers the entire TIR domain.

Last update:

January 2002 / First entry.


Technical section

PROSITE method (with tools and information) covered by this documentation:

TIR, PS50104; TIR domain profile  (MATRIX)


1AuthorsTakeuchi O. Kawai T. Sanjo H. Copeland N.G. Gilbert D.J. Jenkins N.A. Takeda K. Akira S.
TitleTLR6: A novel member of an expanding toll-like receptor family.
SourceGene 231:59-65(1999).
PubMed ID10231569

2AuthorsMitcham J.L. Parnet P. Bonnert T.P. Garka K.E. Gerhart M.J. Slack J.L. Gayle M.A. Dower S.K. Sims J.E.
TitleT1/ST2 signaling establishes it as a member of an expanding interleukin-1 receptor family.
SourceJ. Biol. Chem. 271:5777-5783(1996).
PubMed ID8621445

3AuthorsMuzio M. Ni J. Feng P. Dixit V.M.
TitleIRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling.
SourceScience 278:1612-1615(1997).
PubMed ID9374458

4AuthorsAnderson K.V.
TitleToll signaling pathways in the innate immune response.
SourceCurr. Opin. Immunol. 12:13-19(2000).
PubMed ID10679407

5AuthorsVan der Biezen E.A. Jones J.D.
SourceTrends Biochem. Sci. 23:454-456(1998).

6AuthorsKopp E.B. Medzhitov R.
TitleThe Toll-receptor family and control of innate immunity.
SourceCurr. Opin. Immunol. 11:13-18(1999).
PubMed ID10047546

7AuthorsSlack J.L. Schooley K. Bonnert T.P. Mitcham J.L. Qwarnstrom E.E. Sims J.E. Dower S.K.
TitleIdentification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways.
SourceJ. Biol. Chem. 275:4670-4678(2000).
PubMed ID10671496

8AuthorsXu Y. Tao X. Shen B. Horng T. Medzhitov R. Manley J.L. Tong L.
TitleStructural basis for signal transduction by the Toll/interleukin-1 receptor domains.
SourceNature 408:111-115(2000).
PubMed ID11081518

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