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Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism
Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
ASTAR, Bioinformat Inst, Singapore 138671, Singapore..
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 21, E4213-E4222 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 114, no 21, E4213-E4222 p.
Keyword [en]
aggregation, thrombin, lipopolysaccharides, host defense peptides
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-325696DOI: 10.1073/pnas.1619609114ISI: 000401797800015PubMedID: 28473418OAI: oai:DiVA.org:uu-325696DiVA: diva2:1115996
Funder
Swedish Research Council, 2012-1883Swedish Research Council, 2012-1842The Crafoord FoundationKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research
Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2017-06-27Bibliographically approved

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