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.