Summary: TIR domain
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This is the Wikipedia entry entitled "Toll-Interleukin receptor". More...
Toll-Interleukin receptor Edit Wikipedia article
| TIR domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Structure of the MyD88 TIR domain | |||||||||
| Identifiers | |||||||||
| Symbol | TIR | ||||||||
| Pfam | PF01582 | ||||||||
| InterPro | IPR000157 | ||||||||
| SCOPe | 1fyv / SUPFAM | ||||||||
| OPM superfamily | 289 | ||||||||
| OPM protein | 2mk9 | ||||||||
| Membranome | 7 | ||||||||
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The Toll/interleukin-1 receptor (TIR) homology domain is an intracellular signaling domain found in MyD88, interleukin-1 receptors, Toll receptors and many plant R proteins. It contains three highly conserved regions, and mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. TIR-like motifs are also found in plant proteins thought to be involved in resistance to disease. When activated, TIR domains recruit cytoplasmic adaptor proteins MyD88 (UniProt Q99836) and TOLLIP (Toll interacting protein, UniProt Q9H0E2). In turn, these associate with various kinases to set off signaling cascades.
In Drosophila melanogaster the Toll protein is involved in establishment of dorso-ventral polarity in the embryo. In addition, members of the Toll family play a key role in innate antibacterial and antifungal immunity in insects as well as in mammals. These proteins are type-I transmembrane receptors that share an intracellular 200 residue domain with the interleukin-1 receptor (IL-1R), the Toll/IL-1R homologous region (TIR). The similarity between Toll-like receptors (TLRs) and IL-1R 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] MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain (see InterPro: IPR000488).[1][2][3] Besides the mammalian and Drosophila melanogaster proteins, a TIR domain is also found in a number of plant proteins implicated in host defense.[4] As MyD88, these proteins are cytoplasmic.
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 signaling, whereas box 3 is primarily involved in directing localization of receptor, perhaps through interactions with cytoskeletal elements.[5]
Subfamilies
Human proteins containing this domain
IL18R1; IL18RAP; IL1R1; IL1RAP; IL1RAPL1; IL1RAPL2; IL1RL1; IL1RL2; MYD88; SIGIRR; TLR1; TLR10; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8; TLR9;
References
- ^ a b Bonnert TP, Garka KE, Parnet P, Sims JE, Mitcham JL, Gerhart MJ, Slack JL, Gayle MA, Dower SK (1996). "T1/ST2 signaling establishes it as a member of an expanding interleukin-1 receptor family". J. Biol. Chem. 271 (10): 5777–5783. doi:10.1074/jbc.271.10.5777. PMID 8621445.
- ^ Dixit VM, Muzio M, Ni J, Feng P (1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science. 278 (5343): 1612–1615. doi:10.1126/science.278.5343.1612. PMID 9374458.
- ^ Anderson KV (2000). "Toll signaling pathways in the innate immune response". Curr. Opin. Immunol. 12 (1): 13–19. doi:10.1016/s0952-7915(99)00045-x. PMID 10679407.
- ^ Van der Biezen EA, Jones JD (1998). "Plant disease-resistance proteins and the gene-for-gene concept". Trends Biochem. Sci. 23 (12): 454–456. doi:10.1016/s0968-0004(98)01311-5. PMID 9868361.
- ^ Bonnert TP, Sims JE, Schooley K, Mitcham JL, Slack JL, Dower SK, Qwarnstrom EE (2000). "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 (7): 4670–4678. doi:10.1074/jbc.275.7.4670. PMID 10671496.
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
TIR domain Provide feedback
The Toll/interleukin-1 receptor (TIR) homology domain is an intracellular signalling domain found in MyD88, interleukin 1 receptor and the Toll receptor. It contains three highly-conserved regions, and mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. TIR-like motifs are also found in plant proteins thought to be involved in resistance to disease. When activated, TIR domains recruit cytoplasmic adaptor proteins MyD88 (Q99836) and TOLLIP (Toll interacting protein, Q9H0E2). In turn, these associate with various kinases to set off signalling cascades [3].
Literature references
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Bonnert TP, Garka KE, Parnet P, Sonoda G, Testa JR, Sims JE; , FEBS Lett 1997;402:81-84.: The cloning and characterization of human MyD88: a member of an IL-1 receptor related family. PUBMED:9013863 EPMC:9013863
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Medzhitov R, Preston-Hurlburt P, Janeway CA Jr; , Nature 1997;388:394-397.: A human homologue of the Drosophila Toll protein signals activation of adaptive immunity [see comments] PUBMED:9237759 EPMC:9237759
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Armant MA, Fenton MJ; , Genome Biol 2002;3:REVIEWS3011.: Toll-like receptors: a family of pattern-recognition receptors in mammals. PUBMED:12186654 EPMC:12186654
Internal database links
| SCOOP: | DUF1863 SEFIR TIR-like TIR_2 |
| Similarity to PfamA using HHSearch: | TIR_2 |
External database links
| HOMSTRAD: | TIR |
| SCOP: | 1fyv |
This tab holds annotation information from the InterPro database.
InterPro entry IPR000157
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 [PUBMED:10231569]. Interestingly, MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain [PUBMED:8621445, PUBMED:9374458, PUBMED:10679407]. 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 elements [PUBMED:10671496].
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 [PUBMED:11081518].
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Molecular function | protein binding (GO:0005515) |
| Biological process | signal transduction (GO:0007165) |
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Pfam Clan
This family is a member of clan STIR (CL0173), which has the following description:
Both members of this clan are thought to be involved in TOLL/IL1R-like pathways, by mediating protein-protein interactions between pathway components. The N-termini of SEFIR and TIR domains are similar, but the domains are more divergent towards the C-terminus [1].
The clan contains the following 6 members:
DUF1863 SEFIR TIR TIR-like TIR_2 TIR_3Alignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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| Seed (23) |
Full (13614) |
Representative proteomes | UniProt (22815) |
NCBI (52672) |
Meta (78) |
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| RP15 (1560) |
RP35 (6793) |
RP55 (9914) |
RP75 (13303) |
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| HTML | |||||||||
| PP/heatmap | 1 | ||||||||
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
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| Seed (23) |
Full (13614) |
Representative proteomes | UniProt (22815) |
NCBI (52672) |
Meta (78) |
||||
|---|---|---|---|---|---|---|---|---|---|
| RP15 (1560) |
RP35 (6793) |
RP55 (9914) |
RP75 (13303) |
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| Raw Stockholm | |||||||||
| Gzipped | |||||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logo
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Pfam-B_571 (release 4.1) |
| Previous IDs: | none |
| Type: | Family |
| Sequence Ontology: | SO:0100021 |
| Author: |
Bateman A 
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| Number in seed: | 23 |
| Number in full: | 13614 |
| Average length of the domain: | 159.00 aa |
| Average identity of full alignment: | 23 % |
| Average coverage of the sequence by the domain: | 21.45 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 176 | ||||||||||||
| Family (HMM) version: | 21 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Colour assignments
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Interactions
There is 1 interaction for this family. More...
TIRStructures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the TIR domain has been found. There are 43 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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