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Structural basis for signal transduction by the Toll/interleukin-1 receptor domains

Abstract

Toll-like receptors (TLRs) and the interleukin-1 receptor superfamily (IL-1Rs) are integral to both innate and adaptive immunity for host defence1,2,3. These receptors share a conserved cytoplasmic domain4,5, known as the TIR domain. A single-point mutation in the TIR domain of murine TLR4 (Pro712His, the Lpsd mutation) abolishes the host immune response to lipopolysaccharide (LPS)6, and mutation of the equivalent residue in TLR2, Pro681His, disrupts signal transduction in response to stimulation by yeast and Gram-positive bacteria7. 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 Lpsd mutation. Mutagenesis and functional studies confirm that residues in this surface patch are crucial for receptor signalling. The Lpsd 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 downstream MyD88 adapter molecule7,8,9,10,11, and that the Lpsd mutation may abolish receptor signalling by disrupting this recruitment.

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Figure 1: Structures of the TIR domain.
Figure 2: Structural analysis of the TIR domains.
Figure 3: Functional studies of TIR domains.

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Acknowledgements

We thank K. D'Amico and S. Wasserman for setting up the beamline at the Advanced Photon Source (APS) (supported by the US Department of Energy), R. Abramowitz and C. Ogata for setting up the beamline at the National Synchrotron Light Source (NSLS), and the MacCHESS staff for setting up the beamline at CHESS. We thank G. Bhargava, L. Duan and G. Xu for technical help; R. Khayat, G. Jogl, and Z. Yang for help with data collection at the synchrotron sources; H. Wu and W. Hendrickson for discussions; and Columbia University (L.T.) and an NIH grant (J.L.M.) for financial support.

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Correspondence to Liang Tong.

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Xu, Y., Tao, X., Shen, B. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111–115 (2000). https://doi.org/10.1038/35040600

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