A spontaneous mutation of integrin αIIbβ3 (platelet glycoprotein IIb-IIIa) helps define a ligand binding site

Mary Lynn Bajt, Mark H. Ginsberg, Andrew L. Frelinger, Michael C. Berndt, Joseph C. Loftus

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129 Scopus citations


This work characterizes a mutant integrin αIIbβ3 (glycoprotein (GP) IIb-IIIa) from a thrombasthenic patient, ET, whose platelets fail to aggregate in response to stimuli. The nature of the defect was defined by the reduced ability of synthetic peptide ligands, corresponding to the carboxyl terminus of the fibrinogen γ chain (γ402-411) and Arg-Gly-Asp (RGD), to increase the binding of the occupancy-dependent anti-LIBS1 antibody to mutant αIIbβ3 and the reduced binding of mutant αIIbβ3 to an immobilized RGD peptide. In addition, ET's platelets failed to bind the ligand-mimetic monoclonal anti-αIIbβ3, PAC1. DNA sequence analysis of amplified ET genomic DNA revealed a single G → A base change which encoded substitution of R214 by Q in mature β3. Introduction of this point mutation into recombinant wild type αIIbβ3 expressed in Chinese hamster ovary cells reproduced the ET platelet αIIbβ3 deficits in binding of fibrinogen, mAb PAC1, and synthetic peptide ligands. Furthermore, substitution of R214 by Q in the synthetic peptide containing the sequence of β3(211-222) resulted in decreased ability of this peptide to block fibrinogen binding to purified αIIbβ3. These findings suggest that substitution of β3 R214 by Q is responsible for the functional defect in αIIbβ3 and that R214 is proximal to or part of a ligand binding domain in αIIbβ3.

Original languageEnglish (US)
Pages (from-to)3789-3794
Number of pages6
JournalJournal of Biological Chemistry
Issue number6
StatePublished - Feb 25 1992

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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