A cluster of basic amino acid residues in the γ370-381 sequence of fibrinogen comprises a binding site for platelet integrin α IIbβ3 (glycoprotein IIb/IIIa)

Nataly P. Podolnikova, Oleg V. Gorkun, Ralph M. Loreth, Vivien C. Yee, Susan T. Lord, Tatiana P. Ugarova

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Adhesive interactions of platelet integrin αIIbβ 3 with fibrinogen and fibrin are central events in hemostasis and thrombosis. However, the mechanisms by which αIIbβ 3 binds these ligands remain incompletely understood. We have recently demonstrated that αIIbβ3 binds the γ365-383 sequence in the γC-domain of fibrin(ogen). This sequence contains neither the AGDV nor the RGD recognition motifs, known to bind αIIbβ3, suggesting the different specificity of the integrin. Here, using peptide arrays, mutant fibrinogens, and recombinant mutant γC-domains, we have examined the mechanism whereby αIIbβ3 binds γ365-383. The αIIbβ3-binding activity was localized within γ370-381, with two short sequences, γ370 ATWKTR 375 and γ376WYSMKK381, being able to independently bind the integrin. Furthermore, recognition of αIIbβ3 by γ370-381 depended on four basic residues, Lys373, Arg375, Lys380, and Lys 381. Simultaneous replacement of these amino acids and deletion of the γ408AGDV411 sequence in the recombinant γC-domain resulted in the loss of αIIbβ3- mediated platelet adhesion. Confirming the critical roles of the identified residues, abnormal fibrinogen Kaiserslautern, in which γLys380 is replaced by Asn, demonstrated delayed clot retraction and impaired αIIbβ3 binding. Also, a mutant recombinant fibrinogen modeled after the naturally occurring variant Osaka V (γArg375 → Gly) showed delayed clot retraction and reduced binding to purified αIIbβ3. These results identify the γ370-381 sequence of fibrin(ogen) as the binding site for αIIbβ3 involved in platelet adhesion and clot retraction and define the new recognition specificity of this integrin.

Original languageEnglish (US)
Pages (from-to)16920-16930
Number of pages11
JournalBiochemistry
Volume44
Issue number51
DOIs
StatePublished - Dec 27 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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