PROSITE documentation PDOC50104
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 and in diverse bacterial genera (Streptomyces, Caulobacter, Rhizobium, Anabaena, Synechocystis and Bacillus) [5,6].

The TIR domain has been defined as a scaffold that promotes assembly of signaling complexes via protein-protein interactions. However, the scaffolding function may be a recent adaptation. The primordial function of the TIR domain is a self-association-dependent nicotinamide dinucleotide (NAD(+))-cleaving enzyme (NADase) activity that cleaves NAD(+) into nicotinamide (Nam) and ADP-ribose (ADPR), cyclic ADPR (cADPR) or variant cADPR (v-cADPR), with catalytic cleavage executed by a conserved glutamic acid [7,8,9,10].

Structurally, the TIR domain consists of a central five-stranded parallel β-sheet (βA-βE) surrounded by five helices (αA-αE) with connecting loop structures (see <PDB:1FYV>). The loop regions appear to play an important role in mediating the specificity of protein-protein interactions [9,10,11]. 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 [12].

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) [12].
  • 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].
  • Animal SARM1 (sterile α and TIR motif containing 1), a NAD(+) hydrolase (NADase) required for Wallerian degeneration in axons after nerve injury [9].
  • 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:

November 2019 / Text and profile revised.


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.
TitlePlant disease-resistance proteins and the gene-for-gene concept.
SourceTrends. Biochem. Sci. 23:454-456(1998).
PubMed ID9868361

6AuthorsSpear A.M. Loman N.J. Atkins H.S. Pallen M.J.
TitleMicrobial TIR domains: not necessarily agents of subversion?
SourceTrends. Microbiol. 17:393-398(2009).
PubMed ID19716705

7AuthorsKopp E.B. Medzhitov R.
TitleThe Toll-receptor family and control of innate immunity.
SourceCurr. Opin. Immunol. 11:13-18(1999).
PubMed ID10047546

8AuthorsEssuman K. Summers D.W. Sasaki Y. Mao X. Yim A.K.Y. DiAntonio A. Milbrandt J.
TitleTIR Domain Proteins Are an Ancient Family of NAD(+)-Consuming Enzymes.
SourceCurr. Biol. 28:421-430.e4(2018).
PubMed ID29395922

9AuthorsHorsefield S. Burdett H. Zhang X. Manik M.K. Shi Y. Chen J. Qi T. Gilley J. Lai J.-S. Rank M.X. Casey L.W. Gu W. Ericsson D.J. Foley G. Hughes R.O. Bosanac T. von Itzstein M. Rathjen J.P. Nanson J.D. Boden M. Dry I.B. Williams S.J. Staskawicz B.J. Coleman M.P. Ve T. Dodds P.N. Kobe B.
TitleNAD(+) cleavage activity by animal and plant TIR domains in cell death pathways.
SourceScience 365:793-799(2019).
PubMed ID31439792

10AuthorsWan L. Essuman K. Anderson R.G. Sasaki Y. Monteiro F. Chung E.-H. Osborne Nishimura E. DiAntonio A. Milbrandt J. Dangl J.L. Nishimura M.T.
TitleTIR domains of plant immune receptors are NAD(+)-cleaving enzymes that promote cell death.
SourceScience 365:799-803(2019).
PubMed ID31439793

11AuthorsXu 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

12AuthorsSlack 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

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