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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 …