A peptide from the staphylococcal protein Efb binds P-selectin and inhibits the interaction of platelets with leukocytes
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A peptide from the staphylococcal protein Efb binds P-selectin and inhibits the interaction of platelets with leukocytes. / Wallis, Stuart; Wolska, Nina; Englert, Hanna; Posner, Mareike; Upadhyay, Abhishek; Renné, Thomas; Eggleston, Ian; Bagby, Stefan; Pula, Giordano.
In: J THROMB HAEMOST, Vol. 20, No. 3, 03.2022, p. 729-741.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - A peptide from the staphylococcal protein Efb binds P-selectin and inhibits the interaction of platelets with leukocytes
AU - Wallis, Stuart
AU - Wolska, Nina
AU - Englert, Hanna
AU - Posner, Mareike
AU - Upadhyay, Abhishek
AU - Renné, Thomas
AU - Eggleston, Ian
AU - Bagby, Stefan
AU - Pula, Giordano
N1 - This article is protected by copyright. All rights reserved.
PY - 2022/3
Y1 - 2022/3
N2 - AIMS: P-selectin is a key surface adhesion molecule for the interaction of platelets with leukocytes. We have shown previously that the N-terminal domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb) binds to P-selectin and interferes with platelet-leukocyte aggregate formation. Here, we aimed to identify the minimal Efb motif required for binding platelets and to characterize its ability to interfering with the formation of platelet-leukocyte aggregates.METHODS AND RESULTS: Using a library of synthetic peptides, we mapped the platelet-binding site to a continuous 20 amino acid stretch. The peptide Efb68-87 was able to bind to resting and, to a greater extent, thrombin-stimulated platelets in the absence of fibrinogen. Dot blots, pull-down assays and P-selectin glycoprotein ligand-1 (PSGL-1) competitive binding experiments identified P-selectin as the cellular docking site mediating Efb68-87 platelet binding. Accordingly, Efb68-87 did not bind to other blood cells and captured platelets from human whole blood under low shear stress conditions. Efb68-87 did not affect platelet activation as tested by aggregometry, flow cytometry and immunoblotting, but inhibited the formation of platelet-leukocyte aggregates (PLAs). Efb68-87 also interfered with the platelet-dependent stimulation of neutrophil extracellular traps (NETs) formation in vitro.CONCLUSIONS: We have identified Efb68-87 as a novel selective platelet-binding peptide. Efb68-87 binds directly to P-selectin and inhibits interactions of platelets with leukocytes that lead to PLA and NET formation. As PLAs and NETs play a key role in thromboinflammation, Efb68-87 is an exciting candidate for the development of novel selective inhibitors of the proinflammatory activity of platelets.
AB - AIMS: P-selectin is a key surface adhesion molecule for the interaction of platelets with leukocytes. We have shown previously that the N-terminal domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb) binds to P-selectin and interferes with platelet-leukocyte aggregate formation. Here, we aimed to identify the minimal Efb motif required for binding platelets and to characterize its ability to interfering with the formation of platelet-leukocyte aggregates.METHODS AND RESULTS: Using a library of synthetic peptides, we mapped the platelet-binding site to a continuous 20 amino acid stretch. The peptide Efb68-87 was able to bind to resting and, to a greater extent, thrombin-stimulated platelets in the absence of fibrinogen. Dot blots, pull-down assays and P-selectin glycoprotein ligand-1 (PSGL-1) competitive binding experiments identified P-selectin as the cellular docking site mediating Efb68-87 platelet binding. Accordingly, Efb68-87 did not bind to other blood cells and captured platelets from human whole blood under low shear stress conditions. Efb68-87 did not affect platelet activation as tested by aggregometry, flow cytometry and immunoblotting, but inhibited the formation of platelet-leukocyte aggregates (PLAs). Efb68-87 also interfered with the platelet-dependent stimulation of neutrophil extracellular traps (NETs) formation in vitro.CONCLUSIONS: We have identified Efb68-87 as a novel selective platelet-binding peptide. Efb68-87 binds directly to P-selectin and inhibits interactions of platelets with leukocytes that lead to PLA and NET formation. As PLAs and NETs play a key role in thromboinflammation, Efb68-87 is an exciting candidate for the development of novel selective inhibitors of the proinflammatory activity of platelets.
U2 - 10.1111/jth.15613
DO - 10.1111/jth.15613
M3 - SCORING: Journal article
C2 - 34846792
VL - 20
SP - 729
EP - 741
JO - J THROMB HAEMOST
JF - J THROMB HAEMOST
SN - 1538-7933
IS - 3
ER -