Mutation of a Ligand Binding Domain of β3 Integrin: Integral Role of Oxygenated Residues in αIIbβ3 (GPIIb-IIIa) Receptor Function

Mary Lynn Bajt, Joseph C. Loftus

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140 Scopus citations


A single amino acid substitution in β3 (Asp119 → Tyr) abrogates the ligand binding function of β3 integrins and alters the divalent cation conformation of the platelet integrin αIIbβ3 (GPIIb-IIIa). This aspartic acid residue resides within a conserved cluster of oxygenated residues that may provide ligands for the coordination of divalent cations. To assign function to the other oxygenated residues in this group (Ser121, Ser123, Asp126, Asp127, and Ser130), each of these amino acids in β3 was individually substituted by alanine. None of these amino acid substitutions altered heterodimer formation or surface expression. However, the substitutions had differential effects on receptor function. Substitution at positions Asp119 or Ser121 produced a complete loss of receptor function. Cells expressing these mutants failed to adhere to fibrinogen, failed to bind activation-independent ligand-mimetic peptides, and did not bind the ligand-mimetic mAb PAC1 following activation of the receptor. Similarly, cells expressing β3 with a substitution at Ser123 also failed to adhere to fibrinogen and did not bind RGD peptide or mAb PAC1. These cells did retain the capacity to bind an αIIbβ3-specific, high affinity peptidomimetic, but occupancy did not induce the conformational change from resting to activated state observed following occupancy of the wild type receptor. Substitution at positions Asp126, Asp127, or Ser130 had no effect on ligand binding function. These data indicate that Asp119, along with Ser121 and Ser123, plays an integral role in the ligand binding function of αIIbβ3.

Original languageEnglish (US)
Pages (from-to)20913-20919
Number of pages7
JournalJournal of Biological Chemistry
Issue number33
StatePublished - Aug 19 1994

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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