The toll-interleukin-1 receptor (TIR) homology domain is an intracellular signaling domain found in MyD88, SARM1, 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 where they are involved in resistance to disease and in bacteria where they are associated with virulence.[1][2] 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. Some TIR domains have also been found to have intrinsic NAD+ cleavage activity, such as in SARM1.[3][2][4] In the case of SARM1, the TIR NADase activity leads to the production of Nam, ADPR and cADPR and the activation of downstream pathways involved in Wallerian degeneration and neuron death.[3]
| TIR domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Structure of the MyD88 TIR domain | |||||||||
| Identifiers | |||||||||
| Symbol | TIR | ||||||||
| Pfam | PF01582 | ||||||||
| InterPro | IPR000157 | ||||||||
| SCOP2 | 1fyv / SCOPe / SUPFAM | ||||||||
| OPM superfamily | 289 | ||||||||
| OPM protein | 2mk9 | ||||||||
| Membranome | 7 | ||||||||
| |||||||||
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.[5] MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain (see InterPro: IPR000488).[5][6][7] Besides the mammalian and Drosophila melanogaster proteins, a TIR domain is also found in a number of plant proteins implicated in host defense.[8] 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.[9]
Subfamilies
editHuman proteins containing this domain
editIL18R1; IL18RAP; IL1R1; IL1RAP; IL1RAPL1; IL1RAPL2; IL1RL1; IL1RL2; MYD88; SIGIRR; TLR1; TLR10; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8; TLR9; SARM1;
References
edit- ^ Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y, Chen J, et al. (August 2019). "NAD+ cleavage activity by animal and plant TIR domains in cell death pathways". Science. 365 (6455): 793–799. Bibcode:2019Sci...365..793H. doi:10.1126/science.aax1911. hdl:10072/393098. PMID 31439792. S2CID 201616651.
- ^ a b Essuman K, Summers DW, Sasaki Y, Mao X, Yim AK, DiAntonio A, Milbrandt J (February 2018). "TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes". Current Biology. 28 (3): 421–430.e4. doi:10.1016/j.cub.2017.12.024. PMC 5802418. PMID 29395922.
- ^ a b Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J (March 2017). "The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration". Neuron. 93 (6): 1334–1343.e5. doi:10.1016/j.neuron.2017.02.022. PMC 6284238. PMID 28334607.
- ^ DiAntonio A, Milbrandt J, Figley MD (2021). "The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems". Frontiers in Immunology. 12: 752898. doi:10.3389/fimmu.2021.752898. PMC 8494770. PMID 34630431.
- ^ a b Mitcham JL, Parnet P, Bonnert TP, Garka KE, Gerhart MJ, Slack JL, et al. (March 1996). "T1/ST2 signaling establishes it as a member of an expanding interleukin-1 receptor family". The Journal of Biological Chemistry. 271 (10): 5777–5783. doi:10.1074/jbc.271.10.5777. PMID 8621445.
- ^ Muzio M, Ni J, Feng P, Dixit VM (November 1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science. 278 (5343): 1612–1615. Bibcode:1997Sci...278.1612M. doi:10.1126/science.278.5343.1612. PMID 9374458.
- ^ Anderson KV (February 2000). "Toll signaling pathways in the innate immune response". Current Opinion in Immunology. 12 (1): 13–19. doi:10.1016/s0952-7915(99)00045-x. PMID 10679407.
- ^ Van der Biezen EA, Jones JD (December 1998). "Plant disease-resistance proteins and the gene-for-gene concept". Trends in Biochemical Sciences. 23 (12): 454–456. doi:10.1016/s0968-0004(98)01311-5. PMID 9868361.
- ^ Slack JL, Schooley K, Bonnert TP, Mitcham JL, Qwarnstrom EE, Sims JE, Dower SK (February 2000). "Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways". The Journal of Biological Chemistry. 275 (7): 4670–4678. doi:10.1074/jbc.275.7.4670. PMID 10671496.