Antimicrobial effects of helix D-derived peptides of human antithrombin III.

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Antimicrobial effects of helix D-derived peptides of human antithrombin III. / Papareddy, Praveen; Kalle, Martina; Bhongir, Ravi; Mörgelin, Matthias; Malmsten, Martin; Schmidtchen, Artur.

I: Journal of Biological Chemistry, Vol. 289, Nr. 43, 2014, s. 29790-29800.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Papareddy, Praveen ; Kalle, Martina ; Bhongir, Ravi ; Mörgelin, Matthias ; Malmsten, Martin ; Schmidtchen, Artur. / Antimicrobial effects of helix D-derived peptides of human antithrombin III. I: Journal of Biological Chemistry. 2014 ; Vol. 289, Nr. 43. s. 29790-29800.

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TY - JOUR

T1 - Antimicrobial effects of helix D-derived peptides of human antithrombin III.

AU - Papareddy, Praveen

AU - Kalle, Martina

AU - Bhongir, Ravi

AU - Mörgelin, Matthias

AU - Malmsten, Martin

AU - Schmidtchen, Artur

PY - 2014

Y1 - 2014

N2 - Antithrombin III (ATIII) is a key antiproteinase involved in blood coagulation. Previous investigations have shown that ATIII is degraded by Staphylococcus aureus V8 protease, leading to release of heparin binding fragments derived from its D helix. As heparin binding and antimicrobial activity of peptides frequently overlap, we here set out to explore possible antibacterial effects of intact and degraded ATIII. In contrast to intact ATIII, the results showed that extensive degradation of the molecule yielded fragments with antimicrobial activity. Correspondingly, the heparin-binding, helix D-derived, peptide FFFAKLNCRL-YRKANKSSKLV (FFF21) of human ATIII, was found to be antimicrobial against particularly the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa. Fluorescence microscopy and electron microscopy studies demonstrated that FFF21 binds to, and permeabilizes, bacterial membranes. Analogously, FFF21 was found to induce membrane leakage of model anionic liposomes. In vivo, FFF21 significantly reduced P. aeruginosa infection in mice. Additionally, FFF21 displayed anti-endotoxic effects in vitro. Taken together, our results suggest novel roles for ATIII-derived peptide fragments in host defense.

AB - Antithrombin III (ATIII) is a key antiproteinase involved in blood coagulation. Previous investigations have shown that ATIII is degraded by Staphylococcus aureus V8 protease, leading to release of heparin binding fragments derived from its D helix. As heparin binding and antimicrobial activity of peptides frequently overlap, we here set out to explore possible antibacterial effects of intact and degraded ATIII. In contrast to intact ATIII, the results showed that extensive degradation of the molecule yielded fragments with antimicrobial activity. Correspondingly, the heparin-binding, helix D-derived, peptide FFFAKLNCRL-YRKANKSSKLV (FFF21) of human ATIII, was found to be antimicrobial against particularly the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa. Fluorescence microscopy and electron microscopy studies demonstrated that FFF21 binds to, and permeabilizes, bacterial membranes. Analogously, FFF21 was found to induce membrane leakage of model anionic liposomes. In vivo, FFF21 significantly reduced P. aeruginosa infection in mice. Additionally, FFF21 displayed anti-endotoxic effects in vitro. Taken together, our results suggest novel roles for ATIII-derived peptide fragments in host defense.

U2 - 10.1074/jbc.M114.570465

DO - 10.1074/jbc.M114.570465

M3 - Article

VL - 289

SP - 29790

EP - 29800

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 43

ER -