Portal de Periódicos da CAPES

The dsRNA binding site of human Toll-like receptor 3

2006; National Academy of Sciences; Volume: 103; Issue: 23 Linguagem: Inglês

10.1073/pnas.0603245103

1091-6490

Jessica K. Bell, Janine Askins, Pamela R. Hall, David R. Davies, David M. Segal,

RNA and protein synthesis mechanisms

Pathogen recognition by Toll-like receptors (TLRs) initiates innate immune responses that are essential for inhibiting pathogen dissemination and for the development of acquired immunity. The TLRs recognize pathogens with their N-terminal ectodomains (ECD), but the molecular basis for this recognition is not known. Recently we reported the x-ray structure for unliganded TLR3-ECD; however, it has proven difficult to obtain a crystal structure of TLR3 with its ligand, dsRNA. We have now located the TLR3 ligand binding site by mutational analysis. More than 50 single-residue mutations have been generated throughout the TLR3-ECD, but only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions. These mutations locate the dsRNA binding site on the glycan-free, lateral surface of TLR3 toward the C terminus and suggest a model for dsRNA binding and TLR3 activation.