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J. Biol. Chem., Vol. 283, Issue 18, 11861-11865, May 2, 2008

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The Crystal Structure of the Human Toll-like Receptor 10 Cytoplasmic Domain Reveals a Putative Signaling Dimer^*

Tomas Nyman, Pål Stenmark¹, Susanne Flodin, Ida Johansson, Martin Hammarström, and Pär Nordlund²

From the Structural Genomics Consortium and the Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden

The Toll/interleukin-1 receptor (TIR) domain is a highly conserved signaling domain found in the intracellular regions of Toll-like receptors (TLRs), in interleukin-1 receptors, and in several cytoplasmic adaptor proteins. TIR domains mediate receptor signal transduction through recruitment of adaptor proteins and play critical roles in the innate immune response and inflammation. This work presents the 2.2Å crystal structure of the TIR domain of human TLR10, revealing a symmetric dimer in the asymmetric unit. The dimer interaction surface contains residues from the BB-loop, DD-loop, and C-helix, which have previously been identified as important structural motifs for signaling in homologous TLR receptors. The interaction surface is extensive, containing a central hydrophobic patch surrounded by polar residues. The BB-loop forms a tight interaction, where a range of consecutive residues binds in a pocket formed by the reciprocal BB-loop and C-helix. This pocket appears to be well suited for binding peptide substrates, which is consistent with the notion that peptides and peptide mimetics of the BB-loop are inhibitors for TLR signaling. The TLR10 structure is in good agreement with available biochemical data on TLR receptors and is likely to provide a good model for the physiological dimer.

Received for publication, January 3, 2008 , and in revised form, February 26, 2008.

^* The work also supported by a Grant from the Swedish Cancer Society and the Swedish Research Council (to P. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2J67) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ Present address: The Scripps Research Institute, The Stevens Laboratory – SR105, 10550 N. Torrey Pines Rd., La Jolla, CA 92037.

² To whom correspondence should be addressed: Nobels väg 5, 171 77 Stockholm, Sweden Fax: 46-852486850; E-mail: par.nordlund{at}ki.se.

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