The leech product saratin is a potent inhibitor of platelet integrin α2β1 and von Willebrand factor binding to collagen

Tara C. White, Michelle A. Berny, David K. Robinson, Hang Yin, William F. DeGrado, Stephen R. Hanson, Owen J.T. McCarty

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Subendothelial collagen plays an important role, via both direct and indirect mechanisms, in the initiation of thrombus formation at sites of vascular injury. Collagen binds plasma von Willebrand factor, which mediates platelet recruitment to collagen under high shear. Subsequently, the direct binding of the platelet receptors glycoprotein VI and α2β 1 to collagen is critical for platelet activation and stable adhesion. Leeches, have evolved a number of inhibitors directed towards platelet-collagen interactions so as to prevent hemostasis in the host during hematophagy. In this article, we describe the molecular mechanisms underlying the ability of the leech product saratin to inhibit platelet binding to collagen. In the presence of inhibitors of ADP and thromboxane A2, both saratin and 6F1, a blocking α2β1 mAb, abrogated platelet adhesion to fibrillar and soluble collagen. Additionally, saratin eliminated α2β1-dependent platelet adhesion to soluble collagen in the presence of an Src kinase inhibitor. Moreover, saratin prevented platelet-rich plasma adhesion to fibrillar collagen, a process dependent upon both α2β1 and von Willebrand factor binding to collagen. Furthermore, saratin specifically inhibited the binding of the α2 integrin subunit I domain to collagen, and prevented platelet adhesion to collagen under flow to the same extent as observed in the presence of a combination of mAbs to glycoprotein Ib and α2β1. These results demonstrate that saratin interferes with integrin α2β1 binding to collagen in addition to inhibiting von Willebrand factor-collagen binding, presumably by binding to an overlapping epitope on collagen. This has significant implications for the use of saratin as a tool to inhibit platelet-collagen interactions.

Original languageEnglish (US)
Pages (from-to)1481-1491
Number of pages11
JournalFEBS Journal
Volume274
Issue number6
DOIs
StatePublished - Mar 1 2007

Keywords

  • Collagen
  • Platelet
  • Saratin
  • Von Willebrand factor
  • αβ

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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