title: The crystal structure of the human toll-like receptor 10 cytoplasmic domain reveals a putative signaling dimer.
abstract: 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 2.2A 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 alphaC-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 alphaC-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.
authors.affiliation: Structural Genomics Consortium, Karolinska Institute, Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Nyman
authors.forename: Pål
authors.initials: P
authors.lastname: Stenmark
authors.forename: Susanne
authors.initials: S
authors.lastname: Flodin
authors.forename: Ida
authors.initials: I
authors.lastname: Johansson
authors.forename: Martin
authors.initials: M
authors.lastname: Hammarström
authors.forename: Pär
authors.initials: P
authors.lastname: Nordlund
mesh_terms: D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051201:Toll-Like Receptor 10 / Q000737:chemistry*
chemical_list: C475955:TLR10 protein, human; D051201:Toll-Like Receptor 10