Abstract
Toll‐like receptors (TLRs) are an important part of the innate immune system, acting as a first line of defense against many invading pathogens. The ligand known to bind Gallus toll‐like receptor 21 (gTLR21) is the unmethylated cytosine phosphate guanine dideoxy nucleotide motif; however, the evolutionary characteristics and structural biology of gTLR21 are poorly elaborated. Our results suggest that gTLR21 is phylogenetically and evolutionarily related to the TLR11 family and is perhaps a close ortholog of the Mus TLR13. Structural biology of homology modeling of the gTLR21 ectodomain structure suggests that it has no Z‐loop like that seen in Mus TLR9. The cytosolic toll‐IL‐1 receptor region of gTLR21 contains a central 4‐stranded parallel β‐sheet (βA‐βD) surrounded by 5 α‐helices (αA‐αE) on both sides, a highly conserved structure also seen in other TLRs. Molecular docking analysis reveals that the gTLR21 ectodomain has the potential to distinguish between different ligands. Homodimer analysis results also suggest that Phe842 and Pro844 of the BB loop and Cys876 of the αC helix in gTLR21 are conserved in other cytosolic toll‐IL‐1 receptor domains of other TLRs and may contribute to the docking of homodimers. Our study on the evolutionary characteristics and structural biology of gTLR21 reveals that the molecule may have a broader role to play in innate immune system; however, further experimental validation is required to confirm our findings.
Highlights
Toll‐like receptors (TLRs), which are fundamental sensor molecules in the innate immune system, are membrane‐bound receptors located on the cell surface or in endocytic compartments and can recognize a wide range of pathogen‐associated molecular patterns (PAMPs).[1]
All of TLRs usually contain a series of leucine‐rich repeat (LRR) motifs, a Abbreviations: CpG‐DNA, cytosine phosphate guanine dideoxy nucleotide motif; ECD, ectodomain; Gallus toll‐like receptor 21 (gTLR21), Gallus TLR21; IL‐1, interleukin‐1; IRF7, Interferon regulatory factor 7; LRR, leucine‐rich repeat; LRRhs, highly conserved leucine‐rich repeat segments; LRRvs, variable leucine‐rich repeat segment; MyD88, Myeloid differentiation primary response gene 88; PAMPs, pathogen‐associated molecular patterns; ssRNA, single‐stranded RNA; TIR, cytosolic Toll‐IL‐1 receptor region; TLR, Toll‐like receptors Hongping Wu, Hai Wang, and Wuqi Jiang contributed to this work
The gTLR21 owns high amino acid identities to Anser TLR21, it is possible that TLR21 among avians are highly orthologue and the avian TLR21s are closely related to reptilian
Summary
Toll‐like receptors (TLRs), which are fundamental sensor molecules in the innate immune system, are membrane‐bound receptors located on the cell surface or in endocytic compartments and can recognize a wide range of pathogen‐associated molecular patterns (PAMPs).[1]. The LRR motifs in the ectodomains (ECDs) of different TLRs can recognize different PAMPs as “ligands,” including molecules such as lipids, lipoproteins, proteins, and nucleic acids derived from a wide range of microbes such as bacteria, viruses, parasites, and fungi.[2] the TIR domains of TLRs can trigger downstream signaling pathways to induce the release and production of inflammatory cytokines, type I interferon, and other immune factors. These reactions mediate defensive responses such as inflammation and activate antigen‐specific adaptive immune responses.[3]. A total of 13 TLRs (TLRs 1‐13) have been identified in mammals, mainly in mice and humans; the expression
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