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

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.

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.

Department of Biological Sciences Columbia University, New York, 10027 , New York, USA

Yingwu Xu, Xiao Tao, Baohe Shen, James L. Manley & Liang Tong

Section of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

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