Molecular basis of the functional differences between soluble human versus murine MD-2: Role of Val135 in transfer of lipopolysaccharide from CD14 to MD-2 Articles uri icon


  • Vašl, J.
  • Oblak, A.
  • Peternelj, T.T.
  • Martín-Santamaría, S.
  • Gioannini, T.L.
  • Weiss, J.P.
  • Jerala, R.

publication date

  • March 2016

start page

  • 2309

end page

  • 2318


  • 5


  • 196

International Standard Serial Number (ISSN)

  • 0022-1767

Electronic International Standard Serial Number (EISSN)

  • 1550-6606


  • Myeloid differentiation factor 2 (MD-2) is an extracellular protein, associated with the ectodomain of TLR4, that plays a critical role in the recognition of bacterial LPS. Despite high overall structural and functional similarity, human (h) and murine (m) MD-2 exhibit several species-related differences. hMD-2 is capable of binding LPS in the absence of TLR4, whereas mMD-2 supports LPS responsiveness only when mMD-2 and mTLR4 are coexpressed in the same cell. Previously, charged residues at the edge of the LPS binding pocket have been attributed to this difference. In this study, site-directed mutagenesis was used to explore the hydrophobic residues within the MD-2 binding pocket as the source of functional differences between hMD-2 and mMD-2. Whereas decreased hydrophobicity of residues 61 and 63 in the hMD-2 binding pocket retained the characteristics of wild-type hMD-2, a relatively minor change of valine to alanine at position 135 completely abolished the binding of LPS to the hMD-2 mutant. [...]


  • Biology and Biomedicine


  • hydrophobic residues;circulating md-2; binding of lps; tlr4; molecular structure; inflammatory and immune diseases