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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Uppsala universitet, Historiska institutionen
  • University of Copenhagen
  • National University of Singapore
  • Nanyang Technological University
  • Skåne University Hospital
  • Agency for Science, Technology and Research: Bioinformatics Institute (A*STAR BII)
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

Nyckelord

Originalspråkengelska
Sidor (från-till)E4213-E4222
TidskriftProceedings of the National Academy of Sciences of the United States of America
Volym114
Utgivningsnummer21
StatusPublished - 2017 maj 23
PublikationskategoriForskning
Peer review utfördJa

Relaterad forskningsoutput

Finja Hansen, 2018, Lund: Lund University, Faculty of Medicine. 38 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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