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 . 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
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 .
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) .
- 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 .
- Animal SARM1 (sterile α and TIR motif containing 1), a NAD(+) hydrolase
(NADase) required for Wallerian degeneration in axons after nerve injury
- LRR and TIR domains containing proteins from plants. These cytoplasmic
proteins are important in the host response to infection .
We developed a profile that covers the entire TIR domain.
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