Article open access publication

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

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 9, 1, 2018

DOI:10.1038/s41467-018-05242-0, Dimensions: pub.1105533986, PMC: PMC6050251, PMID: 30018388,

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  1. (1) Nanyang Technological University, grid.59025.3b
  2. (2) Bioinformatics Institute, grid.418325.9
  3. (3) Lund University, grid.4514.4
  4. (4) Uppsala University, grid.8993.b
  5. (5) Aarhus University, grid.7048.b, AU
  6. (6) National University of Singapore, grid.4280.e
  7. (7) University of Copenhagen, grid.5254.6, KU
  8. (8) Copenhagen Wound Healing Center, Bispebjerg Hospital, Department of Biomedical Sciences, University of Copenhagen, DK-2400, Copenhagen, Denmark

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Description

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.

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University of Copenhagen

Danish Open Access Indicator

2018: Realized

Research area: Science & Technology

Danish Bibliometrics Indicator

2018: Level 2

Research area: Science & Technology

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Times Cited: 11

Field Citation Ratio (FCR): 3.19

Relative Citation ratio (RCR): 1.25

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