MD-2: the Toll 'gatekeeper' in endotoxin signalling

Trends Biochem Sci. 2004 Jun;29(6):294-300. doi: 10.1016/j.tibs.2004.04.008.


Lipopolysaccharide (LPS) from the outer cell wall of Gram-negative bacteria is a potent stimulator of the mammalian innate immune system. The Toll-like receptor 4 (TLR4) pathway triggers the inflammatory responses induced by LPS in a process that requires the interaction of LPS-bound myeloid differentiation-2 (MD-2) with TLR4. Here we propose two possible mechanisms for LPS recognition and signalling that take into account both the structural information available for TLR4 and MD-2, and the determinants of endotoxicity, namely, the acylation and phosphorylation patterns of LPS. In our first model, LPS induces the association of two TLR4-MD-2 heterodimers by binding to two different molecules of MD-2 through the acyl chains of lipid A. In our second model, the binding of LPS to a single TLR4-MD-2 complex facilitates the recruitment of a second TLR4-MD-2 heterodimer. These models contrast with the activation of Drosophila Toll, where the receptor is crosslinked by a dimeric protein ligand.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / metabolism*
  • Carbohydrate Sequence
  • Drosophila
  • Drosophila Proteins / metabolism
  • Endotoxins / metabolism*
  • Humans
  • Lipopolysaccharides / metabolism
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Receptors, Cell Surface / metabolism
  • Signal Transduction
  • Substrate Specificity
  • Toll-Like Receptor 4
  • Toll-Like Receptors


  • Antigens, Surface
  • Drosophila Proteins
  • Endotoxins
  • LY96 protein, human
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors