Advanced

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

Saravanan, Rathi; Holdbrook, Daniel A.; Petrlova, Jitka LU ; Singh, Shalini; Berglund, Nils A.; Choong, Yeu Khai; Kjellström, Sven LU ; Bond, Peter J.; Malmsten, Martin and Schmidtchen, Artur LU (2018) In Nature Communications 9(1).
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
9
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85050392598
ISSN
2041-1723
DOI
10.1038/s41467-018-05242-0
language
English
LU publication?
yes
id
c51b8c61-5739-4fca-ae4b-20c99911657b
date added to LUP
2018-08-15 15:14:14
date last changed
2019-04-10 04:12:01
@article{c51b8c61-5739-4fca-ae4b-20c99911657b,
  abstract     = {<p>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.</p>},
  articleno    = {2762},
  author       = {Saravanan, Rathi and Holdbrook, Daniel A. and Petrlova, Jitka and Singh, Shalini and Berglund, Nils A. and Choong, Yeu Khai and Kjellström, Sven and Bond, Peter J. and Malmsten, Martin and Schmidtchen, Artur},
  issn         = {2041-1723},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides},
  url          = {http://dx.doi.org/10.1038/s41467-018-05242-0},
  volume       = {9},
  year         = {2018},
}