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The dsRNA binding site of human Toll‐like receptor 3
Author(s) -
Bell Jessica K.,
Askins Janine,
Hall Pamela R.,
Davies David R.,
Segal David M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a96-d
Subject(s) - ectodomain , tlr3 , innate immune system , mda5 , leucine rich repeat , biology , toll like receptor , rna silencing , receptor , pattern recognition receptor , pathogen associated molecular pattern , microbiology and biotechnology , flagellin , transmembrane domain , trif , rna , genetics , rna interference , gene
Toll‐like receptors (TLRs) are pattern recognition receptors that act as the innate immune system’s first line of defense by sensing invading pathogen through pathogen associated molecular patterns (PAMPs). TLRs are type I transmembrane receptors with an ectodomain consisting of 19–25 leucine rich repeats and a cytoplasmic toll/IL‐1 receptor/resistance domain. Evolutionarily conserved microbial or viral ligands such as lipotechoic acids, dsRNA, lipopolysaccharide, flagellin, ssRNA and unmethylated CpG motifs are recognized by TLR ectodomains 2, 3, 4, 5, 7 and 9, respectively. The mechanism by which TLRs recognize such a diverse set of ligands within the secondary structural motif of leucine rich repeat motifs remains to be solved. From our recent TLR3 ectodomain crystal structure, we have predicted several potential modes of dsRNA binding. In these studies we will present mutational analysis of our predicted sites. Stimulation assays on mutants allowed validation of whether the sites participate in dsRNA recognition. Direct binding assays of these mutants reveal altered dsRNA:TLR3 ectodomain interactions. From these studies we have revised our model of TLR3 recognition of dsRNA. Research supported by NIH Intramural Research and NIAID Biodefense Award.