The molecular structure of the TLR3 extracellular domain

Bell, Jessica K.; Botos, Istvan; Hall, Pamela R.; Askins, Janine; Shiloach, Joseph; Davies, David R.; Segal, David M.

doi:10.1177/09680519060120060801

Cited by 16 publications

(16 citation statements)

References 19 publications

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“…Each TLR ectodomain contains more than 10 LRR modules that are assembled into an α/β horseshoe fold with an inner surface of parallel β-sheet, an outer surface of α-helices or long loops, and a hydrophobic core between that is packed with many leucine residues. Crystal structures of most TLR ectodomains, alone or in complex with their ligands, are now available (13–20). These structures include those of TLR3, the TLR1/TLR2 complex, and the TLR2/TLR6 complex, which have been reviewed extensively (6, 21–23), and those in the TLR4, TLR5, and TLR8 systems, which were reported more recently (16, 18–20).…”

Section: The Toll-like Receptor/il-1r Signaling Pathwaymentioning

confidence: 99%

Structural Biology of Innate Immunity

Yin

et al. 2015

Annu. Rev. Immunol.

101

103

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Innate immune responses depend on timely recognition of pathogenic or danger signals by multiple cell surface or cytoplasmic receptors and transmission of signals for proper counteractions through adaptor and effector molecules. At the forefront of innate immunity are four major signaling pathways, including those elicited by Toll-like receptors, RIG-I-like receptors, inflammasomes, or cGAS, each with its own cellular localization, ligand specificity, and signal relay mechanism. They collectively engage a number of overlapping signaling outcomes, such as NF-κB activation, interferon response, cytokine maturation, and cell death. Several proteins often assemble into a supramolecular complex to enable signal transduction and amplification. In this article, we review the recent progress in mechanistic delineation of proteins in these pathways, their structural features, modes of ligand recognition, conformational changes, and homo- and hetero-oligomeric interactions within the supramolecular complexes. Regardless of seemingly distinct interactions and mechanisms, the recurring themes appear to consist of autoinhibited resting-state receptors, ligand-induced conformational changes, and higher-order assemblies of activated receptors, adaptors, and signaling enzymes through conserved protein-protein interactions.

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Section: The Toll-like Receptor/il-1r Signaling Pathwaymentioning

confidence: 99%

Structural Biology of Innate Immunity

Yin

et al. 2015

Annu. Rev. Immunol.

101

103

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“…Viral dsRNA are recognized by the TLR3 subfamily, whereas nucleic acid PAMPs are recognized by the TLR7 subfamily (TLR7, 8 and 9) [9]. Currently, five crystallographic structures of TLR ECDs and their ligand complexes have been reported [10], [11], [12], [13], [14], [15], [16]. Of those, four were found to be complexed with agonistic ligands, whereas the remaining one was complexed with a co-receptor and an antagonistic ligand.…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Species-Specific Ligand Recognition in Toll-Like Receptor 8 Signaling: A Hypothesis

et al. 2011

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Toll-like receptors (TLRs) play a central role in the innate immune response by recognizing conserved structural patterns in a variety of microbes. TLRs are classified into six families, of which TLR7 family members include TLR7, 8, and 9, which are localized to endolysosomal compartments recognizing viral infection in the form of foreign nucleic acids. In our current study, we focused on TLR8, which has been shown to recognize different types of ligands such as viral or bacterial ssRNA as well as small synthetic molecules. The primary sequences of rodent and non-rodent TLR8s are similar, but the antiviral compound (R848) that activates the TLR8 pathway is species-specific. Moreover, the factors underlying the receptor's species-specificity remain unknown. To this end, comparative homology modeling, molecular dynamics simulations refinement, automated docking and computational mutagenesis studies were employed to probe the intermolecular interactions between this anti-viral compound and TLR8. Furthermore, comparative analyses of modeled TLR8 (rodent and non-rodent) structures have shown that the variation mainly occurs at LRR14-15 (undefined region); hence, we hypothesized that this variation may be the primary reason for the exhibited species-specificity. Our hypothesis was further bolstered by our docking studies, which clearly showed that this undefined region was in close proximity to the ligand-binding site and thus may play a key role in ligand recognition. In addition, the interface between the ligand and TLR8s varied depending upon the amino acid charges, free energy of binding, and interaction surface. Therefore, our current work provides a hypothesis for previous in vivo studies in the context of TLR signaling.

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“…The structure of the human TLR3 ectodomain revealed a horseshoe shape, characteristic of proteins containing multiple leucine-rich repeats [50]. The conserved L412 residue exists within the TLR3 ectodomain, and L412F mutation is very likely to be disruptive to the structure and function of TLR3 [40].…”

Section: Discussionmentioning

confidence: 99%

Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

et al. 2017

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Intracellular Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and activates antiviral immune responses through the production of type I interferons (IFNs) and inflammatory cytokines. This receptor binds to dsRNA molecules produced during human cytomegalovirus (HCMV) replication. TLR7 senses viral single-stranded RNA (ssRNA) in endosomes, and it can interact with endogenous RNAs. We determined the genotype distribution of single-nucleotide polymorphisms (SNPs) within the TLR3 and TLR7 genes in children with HCMV infection and the relationship between TLR polymorphisms and viral infection. We genotyped 59 children with symptomatic HCMV infection and 78 healthy individuals for SNPs in the TLR3 (rs3775290, c.1377C>T, F459F; rs3775291, c.1234C>T, L412F; rs3775296, c.-7C>A) and TLR7 (rs179008, c.32A>T, Q11L; rs5741880, c.3+1716G>T) genes. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and capillary electrophoresis. The HCMV DNA load was quantified by real-time PCR. We found an increased frequency of the heterozygous genotype TLR3 L412F in children with HCMV infection compared with uninfected cases. In individuals with a mutation present in at least one allele of the L412F SNP, an increased risk of HCMV disease was found, and this result remained highly significant after Bonferroni’s correction for multiple testing (Pc < 0.001). The heterozygous genotype of this SNP was associated with the increased risk of HCMV disease in an adjusted model that included the HCMV DNA copy number in whole blood and urine (P < 0.001 and P = 0.008, respectively). Moreover, those with a heterozygous genotype of rs3775296 showed an increased relative risk of HCMV infection (P = 0.042), but this association did not reach statistical significance after correction for multiple testing. In contrast, the rs3775290 SNP of TLR3 and TLR7 SNPs were not related to viral infection. A moderate linkage disequilibrium (LD) was observed between the SNPs rs3775291 and rs3775296 (r2 = 0.514). We suggest that the L412F polymorphism in the TLR3 gene could be a genetic risk factor for the development of HCMV disease.

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The molecular structure of the TLR3 extracellular domain

Cited by 16 publications

References 19 publications

Structural Biology of Innate Immunity

Structural Biology of Innate Immunity

Comparative Analysis of Species-Specific Ligand Recognition in Toll-Like Receptor 8 Signaling: A Hypothesis

Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

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