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Proc Natl Acad Sci U S A. 2017 May 23;114(21):E4213-E4222. doi: 10.1073/pnas.1619609114. Epub 2017 May 4.

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

Author information

1
Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden; jitka.petrlova@med.lu.se.
2
Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden.
3
Bioinformatics Institute (A*STAR), 138671 Singapore.
4
Division of Infection Medicine, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden.
5
Department of Pharmacy, Uppsala University, SE-75123 Uppsala, Sweden.
6
Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.
7
Department of Biological Sciences, National University of Singapore, 117543 Singapore.
8
Dermatology, Lee Kong Chian School of Medicine, Nanyang Technological University, 636921 Singapore.
9
Dermatology, Skane University Hospital, SE-22185 Lund, Sweden.

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.

KEYWORDS:

aggregation; host defense peptides; lipopolysaccharides; thrombin

PMID:
28473418
PMCID:
PMC5448181
DOI:
10.1073/pnas.1619609114
[Indexed for MEDLINE]
Free PMC Article

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