Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides

Research output: Contribution to journalArticle

Abstract

Thrombin-derived C-terminal peptides (TCPs) of about 2 kDa are present in wounds, where they exert anti-endotoxic functions. Employing a combination of nuclear magnetic resonance spectroscopy (NMR), biophysical, mass spectrometry and cellular studies combined with in silico multiscale modelling, we here determine the bound conformation of HVF18 (HVFRLKKWIQKVIDQFGE), a TCP generated by neutrophil elastase, in complex with bacterial lipopolysaccharide (LPS) and define a previously undisclosed interaction between TCPs and human CD14. Further, we show that TCPs bind to the LPS-binding hydrophobic pocket of CD14 and identify the peptide region crucial for TCP interaction with LPS and CD14. Taken together, our results demonstrate the role of structural transitions in LPS complex formation and CD14 interaction, providing a molecular explanation for the previously observed therapeutic effects of TCPs in experimental models of bacterial sepsis and endotoxin shock.

Details

Authors
Organisations
External organisations
  • Nanyang Technological University
  • Agency for Science, Technology and Research: Bioinformatics Institute (A*STAR BII)
  • Uppsala University
  • Aarhus University
  • National University of Singapore
  • University of Copenhagen
  • Lee Kong Chian School of Medicine
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biophysics
Original languageEnglish
Article number2762
JournalNature Communications
Volume9
Issue number1
Publication statusPublished - 2018 Jul 17
Publication categoryResearch
Peer-reviewedYes