Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/83618
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dc.contributor.authorPetrlova, Jitkaen
dc.contributor.authorHansen, Finja C.en
dc.contributor.authorvan der Plas, Mariena J. A.en
dc.contributor.authorHuber, Roland G.en
dc.contributor.authorMörgelin, Matthiasen
dc.contributor.authorMalmsten, Martinen
dc.contributor.authorBond, Peter J.en
dc.contributor.authorSchmidtchen, Arturen
dc.date.accessioned2017-07-03T02:44:34Zen
dc.date.accessioned2019-12-06T15:26:52Z-
dc.date.available2017-07-03T02:44:34Zen
dc.date.available2019-12-06T15:26:52Z-
dc.date.issued2017en
dc.identifier.citationPetrlova, J., Hansen, F. C., van der Plas, M. J. A., Huber, R. G., Mörgelin, M., Malmsten, M., et al. (2017). 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, 114(21), E4213-E4222.en
dc.identifier.issn0027-8424en
dc.identifier.urihttps://hdl.handle.net/10356/83618-
dc.description.abstractEffective 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.en
dc.format.extent37 p.en
dc.language.isoenen
dc.relation.ispartofseriesProceedings of the National Academy of Sciences of the United States of Americaen
dc.rights© 2017 The Author(s) (Published by National Academy of Sciences). This is the author created version of a work that has been peer reviewed and accepted for publication by Proceedings of the National Academy of Sciences of the United States of America, The Author(s) (Published by National Academy of Sciences). It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1073/pnas.1619609114].en
dc.subjectAggregationen
dc.subjectHost defense peptidesen
dc.titleAggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanismen
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en
dc.identifier.doi10.1073/pnas.1619609114en
dc.description.versionAccepted Versionen
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Appears in Collections:LKCMedicine Journal Articles

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