|Nature (2000) 408(6808):111-5|
|Northeast Structural Genomics Consortium|
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Toll-like receptors (TLRs) and the interleukin-1 receptor superfamily (IL-1Rs) are integral to both innate and adaptive immunity for host defence. ...
These receptors share a conserved cytoplasmic domain, known as the TIR domain. A single-point mutation in the TIR domain of murine TLR4 (Pro712His, the Lps(d) mutation) abolishes the host immune response to lipopolysaccharide (LPS), and mutation of the equivalent residue in TLR2, Pro681His, disrupts signal transduction in response to stimulation by yeast and gram-positive bacteria. Here we report the crystal structures of the TIR domains of human TLR1 and TLR2 and of the Pro681His mutant of TLR2. The structures have a large conserved surface patch that also contains the site of the Lps(d) mutation. Mutagenesis and functional studies confirm that residues in this surface patch are crucial for receptor signalling. The Lps(d) mutation does not disturb the structure of the TIR domain itself. Instead, structural and functional studies indicate that the conserved surface patch may mediate interactions with the down-stream MyD88 adapter molecule, and that the Lps(d) mutation may abolish receptor signalling by disrupting this recruitment.
|metabolism chemistry |
|Crystallography, X-Ray Humans Protein Structure, Tertiary Amino Acid Sequence Animals Drosophila Proteins Models, Molecular Molecular Sequence Data Protein Binding Cloning, Molecular Protein Conformation Structure-Activity Relationship Mice Recombinant Fusion Proteins Point Mutation Membrane Glycoproteins Receptors, Cell Surface Drosophila Receptors, Interleukin-1 Toll-Like Receptor 1 Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptors |
|530 (Last update: 11/10/2018 5:01:37pm)|
|Nature. 2000 Nov 2;408(6808):111-5.|