Identification of a novel binding site for platelet integrins α IIbβ3 (GPIIbIIIa) and α5β 1 in the γC-domain of fibrinogen

Nataly P. Podolnikova, Valentin P. Yakubenko, George L. Volkov, Edward F. Plow, Tatiana P. Ugarova

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The interactions of platelets with fibrinogen mediate a variety of responses including adhesion, platelet aggregation, and fibrin clot retraction. Whereas it was assumed that interactions of the platelet integrin α IIbβ3 with the AGDV sequence in the γC-domain of fibrinogen and/or RGD sites in the Aα chains are involved in clot retraction and adhesion, recent data demonstrated that fibrinogen lacking these sites still supported clot retraction. These findings suggested that an unknown site in fibrinogen and/or other integrins participate in clot retraction. Here we have identified a sequence within γC that mediates binding of fibrinogen to platelets. Synthetic peptide duplicating the 365-383 sequence in γC, designated P3, efficiently inhibited clot retraction in a dose-dependent manner. Furthermore, P3 supported platelet adhesion and was an effective inhibitor of platelet adhesion to fibrinogen fragments. Analysis of overlapping peptides spanning P3 and mutant recombinant γC-domains demonstrated that the P3 activity is contained primarily within γ370-383. Integrins αIIbβ3 and α 5β1 were implicated in recognition of P3, since platelet adhesion to the peptide was blocked by function-blocking monoclonal antibodies against these receptors. Direct evidence that α IIbβ3 and α5β1 bind P3 was obtained by selective capture of these integrins from platelet lysates using a P3 affinity matrix. Thus, these data suggest that the P3 sequence in the γC-domain of fibrinogen defines a previously unknown recognition specificity of αIIbβ3 and α 5β1 and may function as a binding site for these integrins.

Original languageEnglish (US)
Pages (from-to)32251-32258
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number34
DOIs
StatePublished - Aug 22 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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