Peptide Antagonists for P-selectin Discriminate between Sulfatide-Dependent Platelet Aggregation and PSGL-1-Mediated Cell Adhesion

Suzanne J A Korporaal, Tom J M Molenaar, Bianca C H Lutters, Illiana Meurs, Sandra Drost-Verhoef, Johan Kuiper, Theo J C van Berkel, Erik A L Biessen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Web of Science)

Abstract

BACKGROUND: Membrane-exposed sulfatides are proposed to contribute to P-selectin-dependent platelet aggregation. Here, we demonstrated that P-selectin-mediated platelet aggregation on a collagen-coated surface under flow indeed depended on sulfatides and that this interaction differed considerably from the interaction of P-selectin with P-selectin Glycoprotein Ligand-1 (PSGL-1), which underlies leukocyte-endothelium adhesion.

METHODS AND RESULTS: Upon platelet activation, sulfatides were translocated to the platelet surface to form focal hot-spots. Interestingly, P-selectin was observed to exclusively interact with liposomes with a sulfatide density higher than 21% (w/w), indicating that the binding profile of P-selectin for sulfatide-rich liposomes was dependent on sulfatide density. Sulfatide-liposome binding to P-selectin and sulfatide/P-selectin-dependent platelet aggregation was blunted by peptide antagonists, carrying the EWVDV motif within N-terminal extensions, such as CDVEWVDVSC (half maximal inhibitory concentration IC50 = 0.2 μM), but not by the EWVDV core motif itself (IC50 > 1000 μM), albeit both being equally potent inhibitors of PSGL-1/P-selectin interaction (IC50= 7-12 μM).

CONCLUSIONS: Our data suggest that the sulfatide/P-selectin interaction implicates multiple binding pockets, which only partly overlap with that of PSGL-1. These observations open ways to selectively interfere with sulfatide/P-selectin-dependent platelet aggregation without affecting PSGL-1-dependent cell adhesion.

Original languageEnglish
Article number1266
Number of pages15
JournalJournal of Clinical Medicine
Volume8
Issue number8
DOIs
Publication statusPublished - 20 Aug 2019

Keywords

  • antagonists
  • peptides
  • platelets
  • P-selectin
  • sulfatide
  • GRANULE MEMBRANE-PROTEIN
  • BINDING
  • RECOGNITION
  • GMP-140
  • PSGL-1
  • LIGAND
  • GLYCOLIPIDS
  • NEUTROPHILS
  • ACTIVATION
  • EXPRESSION

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