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Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2

Umeharu Ohto1, Koichi Fukase, Kensuke Miyake

  • 1Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|April 26, 2012
PubMed

Insights

Structural analysis reveals how lipopolysaccharide (LPS) and lipid IVa activate toll-like receptor 4 (TLR4) differently in mice versus humans. This explains species-specific immune responses to endotoxin variants.

Area of Science:

  • Immunology
  • Structural Biology
  • Molecular Biology

Background:

  • Lipopolysaccharide (LPS), or endotoxin, is a key activator of innate immunity via toll-like receptor 4 (TLR4) and its coreceptor MD-2.
  • MD-2's hydrophobic cavity binds lipid A, the active component of LPS, mediating TLR4 activation.
  • Tetraacylated lipid IVa, a lipid A precursor, exhibits differential activity: weak agonist in mice and antagonist in humans, with mechanisms unclear.

Purpose of the Study:

  • To elucidate the structural basis for species-specific agonistic/antagonistic activities of LPS and lipid IVa.
  • To understand the ligand-binding and dimerization mechanisms of TLR4/MD-2 complexes with diverse lipid variants.

Main Methods:

  • Determined crystal structures of mouse TLR4/MD-2 complexed with LPS and lipid IVa at 2.5 and 2.7 Å resolutions.
  • Comparative structural analysis of mouse and human TLR4/MD-2 complexes with LPS and lipid IVa.

Main Results:

  • Mouse TLR4/MD-2/LPS formed an agonistic 'm'-shaped 2:2:2 complex, similar to human complexes.
  • Mouse TLR4/MD-2/lipid IVa also adopted an agonistic 2:2:2 architecture, with lipid IVa occupying a similar binding site as LPS despite lacking two acyl chains.
  • Human MD-2 exhibited a distinct, antagonistic binding mode for lipid IVa compared to mouse MD-2.

Conclusions:

  • Structural data confirms lipid IVa's agonistic role in mouse TLR4/MD-2 activation.
  • Demonstrates distinct binding mechanisms of lipid IVa by mouse versus human MD-2, explaining species-specific immune responses.
  • Provides insights into the ligand binding and dimerization dynamics of TLR4/MD-2 with structurally varied LPS analogs.

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