Characterization of a gain of function mutation of integrin αIIbβ3 (platelet glycoprotein IIb-IIIa)

Mary Lynn Bajt, Joseph C. Loftus, Meinrad P. Gawaz, Mark H. Ginsberg

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33 Scopus citations


Integrin αIIbβ3 (platelet glycoprotein IIb-IIIa) is a prototype of integrins involved in cellular adhesive functions. As part of a structure-function analysis of this molecule, we constructed a mutant, designated αIIbβ31-2), by replacing 6 amino acids within a putative ligand binding domain of the β3 subunit with sequences derived from β1. The alteration did not affect the capacity of β31-2) to combine with transfected αIIb, nor did it cause it to combine with endogenous α5. Integrin αIIbβ31-2) was in a "resting" state on Chinese hamster ovary cells as judged by minimal binding of an activation-specific anti-αIIbβ3, PAC1. Nevertheless, cells expressing αIIbβ31-2) spontaneously bound fibrinogen with low affinity (Kα = (4.85 ± 0.84) × 106 M-1). Activation with an anti-β3 antibody (monoclonal antibody 62) resulted in a 10-fold increase in fibrinogen binding affinity (Kα = (4.55 ± 0.77) × 107 M-1), which was 3-fold greater than fibrinogen binding to activated wild type αIIbβ3 (Kα = (1.66 ± 0.33) × 107 M-1, F= 7.46, p = 0.008). The mutant receptor also bound fibrinogen mimetic peptide ligands with enhanced affinity as measured by the conformation-specific antibody, anti-LIBS1. This indicates that the increased affinity for fibrinogen was caused by enhanced interaction of αIIbβ31-2) with known recognition sequences in fibrinogen. Thus, this gain of function mutant augments ligand binding function, supporting a role for this region of the β subunit in ligand binding to integrins.

Original languageEnglish (US)
Pages (from-to)22211-22216
Number of pages6
JournalJournal of Biological Chemistry
Issue number31
StatePublished - Nov 5 1992

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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