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18  structures 330  species 1  interaction 4612  sequences 676  architectures

Family: TIR (PF01582)

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
PDB 2js7 EBI.png
Structure of the MyD88 TIR domain
Identifiers
Symbol TIR
Pfam PF01582
InterPro IPR000157
SCOP 1fyv
SUPERFAMILY 1fyv

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 (UniProt Q99836) and TOLLIP (Toll interacting protein, UniProt Q9H0E2). In turn, these associate with various kinases to set off signalling 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 (LTRs) 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] Interestingly, MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain (see 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[edit]

Human proteins containing this domain[edit]

IL18R1; IL18RAP; IL1R1; IL1RAP; IL1RAPL1; IL1RAPL2; IL1RL1; IL1RL2; MYD88; SIGIRR; TLR1; TLR10; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8; TLR9;

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ Anderson KV (2000). "Toll signaling pathways in the innate immune response". Curr. Opin. Immunol. 12 (1): 13–19. PMID 10679407. 
  4. ^ Van der Biezen EA, Jones JD (1998). "Plant disease-resistance proteins and the gene-for-gene concept". Trends Biochem. Sci. 23 (12): 454–456. PMID 9868361. 
  5. ^ 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. 


This article incorporates text from the public domain Pfam and InterPro IPR000157


This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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

  1. 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

  2. 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

  3. Armant MA, Fenton MJ; , Genome Biol 2002;3:REVIEWS3011.: Toll-like receptors: a family of pattern-recognition receptors in mammals. PUBMED:12186654 EPMC:12186654


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000157

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 (LTRs) and IL-1R 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 [PUBMED:8621445]. Interestingly, MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain (see INTERPRO) [PUBMED:8621445, PUBMED:9374458, PUBMED:10679407]. Besides the mammalian and Drosophila melanogaster proteins, a TIR domain is also found in a number of plant proteins implicated in host defence [PUBMED:9868361]. 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 signalling, whereas box 3 is primarily involved in directing localization of receptor, perhaps through interactions with cytoskeletal elements [PUBMED:10671496].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

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 4 members:

DUF1863 SEFIR TIR TIR_2

Alignments

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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(45)
Full
(4612)
Representative proteomes NCBI
(5111)
Meta
(86)
RP15
(512)
RP35
(992)
RP55
(1303)
RP75
(1819)
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  Seed
(45)
Full
(4612)
Representative proteomes NCBI
(5111)
Meta
(86)
RP15
(512)
RP35
(992)
RP55
(1303)
RP75
(1819)
Alignment:
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Sequence:
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  Seed
(45)
Full
(4612)
Representative proteomes NCBI
(5111)
Meta
(86)
RP15
(512)
RP35
(992)
RP55
(1303)
RP75
(1819)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

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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.

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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 View help on the curation process

Seed source: Pfam-B_571 (release 4.1)
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 45
Number in full: 4612
Average length of the domain: 129.70 aa
Average identity of full alignment: 23 %
Average coverage of the sequence by the domain: 17.89 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.2 21.2
Trusted cut-off 21.2 21.2
Noise cut-off 21.1 21.1
Model length: 141
Family (HMM) version: 15
Download: download the raw HMM for this family

Species distribution

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Interactions

There is 1 interaction for this family. More...

TIR

Structures

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 18 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 seqence.

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