Article open access publication

Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences, ISSN 0027-8424

Volume 114, 21, 2017

DOI:10.1073/pnas.1619609114, Dimensions: pub.1085203602, PMC: PMC5448181, PMID: 28473418,

Affiliations

Organisations

  1. (1) Lund University, grid.4514.4
  2. (2) Bioinformatics Institute, grid.418325.9
  3. (3) University of Copenhagen, grid.5254.6, KU
  4. (4) Uppsala University, grid.8993.b
  5. (5) National University of Singapore, grid.4280.e
  6. (6) Nanyang Technological University, grid.59025.3b
  7. (7) Skåne University Hospital, grid.411843.b

Countries

Singapore

Sweden

Denmark

Continents

Asia

Europe

Description

Effective control of endotoxins and bacteria is crucial for normal wound healing. During injury, the key enzyme thrombin is formed, leading to generation of fibrin. Here, we show that human neutrophil elastase cleaves thrombin, generating 11-kDa thrombin-derived C-terminal peptides (TCPs), which bind to and form amorphous amyloid-like aggregates with both bacterial lipopolysaccharide (LPS) and gram-negative bacteria. In silico molecular modeling using atomic resolution and coarse-grained simulations corroborates our experimental observations, altogether indicating increased aggregation through LPS-mediated intermolecular contacts between clusters of TCP molecules. Upon bacterial aggregation, recombinantly produced TCPs induce permeabilization of Escherichia coli and phagocytic uptake. TCPs of about 11 kDa are present in acute wound fluids as well as in fibrin sloughs from patients with infected wounds. We noted aggregation and colocalization of LPS with TCPs in such fibrin material, which indicates the presence of TCP-LPS aggregates under physiological conditions. Apart from identifying a function of proteolyzed thrombin and its fragments, our findings provide an interesting link between the coagulation system, innate immunity, LPS scavenging, and protein aggregation/amyloid formation.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

University of Copenhagen

Danish Open Access Indicator

2017: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2017: Level 2

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 20

Field Citation Ratio (FCR): 4.09

Relative Citation ratio (RCR): 1.95

Open Access Info

Hybrid