Structural Basis for Signal Transduction by the Toll/interleukin-1 Receptor Domains

Nature. 2000 Nov 2;408(6808):111-5. doi: 10.1038/35040600.

Abstract

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 the TIR domain itself. Instead, structural and functional studies indicate that the conserved surface patch may mediate interactions with the down-stream MyD88 adapter molecule, and that the Lps(d) mutation may abolish receptor signalling by disrupting this recruitment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Drosophila
  • Drosophila Proteins*
  • Humans
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Point Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism*
  • Receptors, Interleukin-1 / chemistry
  • Receptors, Interleukin-1 / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Structure-Activity Relationship
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Substances

  • Drosophila Proteins
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Receptors, Interleukin-1
  • Recombinant Fusion Proteins
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Associated data

  • PDB/1FYU
  • PDB/1FYW
  • PDB/1FYX