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

Petrlova, Jitka LU ; Hansen, Finja C. LU ; Van Der Plas, Mariena J.A. LU ; Huber, Roland G.; Mörgelin, Matthias LU ; Malmsten, Martin; Bond, Peter J. and Schmidtchen, Artur LU (2017) In Proceedings of the National Academy of Sciences of the United States of America 114(21). p.4213-4222
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aggregation, Host defense peptides, Lipopolysaccharides, Thrombin
in
Proceedings of the National Academy of Sciences of the United States of America
volume
114
issue
21
pages
4213 - 4222
publisher
National Acad Sciences
external identifiers
  • scopus:85019611584
  • wos:000401797800015
ISSN
0027-8424
DOI
10.1073/pnas.1619609114
language
English
LU publication?
yes
id
8470d876-0437-4574-afae-da58dc443b7f
date added to LUP
2017-06-08 15:44:37
date last changed
2018-01-07 12:06:44
@article{8470d876-0437-4574-afae-da58dc443b7f,
  abstract     = {<p>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.</p>},
  author       = {Petrlova, Jitka and Hansen, Finja C. and Van Der Plas, Mariena J.A. and Huber, Roland G. and Mörgelin, Matthias and Malmsten, Martin and Bond, Peter J. and Schmidtchen, Artur},
  issn         = {0027-8424},
  keyword      = {Aggregation,Host defense peptides,Lipopolysaccharides,Thrombin},
  language     = {eng},
  month        = {05},
  number       = {21},
  pages        = {4213--4222},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism},
  url          = {http://dx.doi.org/10.1073/pnas.1619609114},
  volume       = {114},
  year         = {2017},
}