Ligand binding to integrin α(IIb)β3 is dependent on a MIDAS-like domain in the β3 subunit

Eileen Collins Tozer, Robert C. Liddington, Michael J. Sutcliffe, Allister H. Smeeton, Joseph C. Loftus

Research output: Contribution to journalArticle

158 Scopus citations

Abstract

Substitution of β3 residue Asp119, Ser121, or Ser123 results in a loss of the ligand binding function of integrin α(IIb)β3. Homologous residues in other integrin β subunits are similarly critical for ligand binding function. This DXSXS motif is also present in the I domain of certain integrin α subunits, where it constitutes a portion of the unique metal ion- dependent adhesion site (MIDAS). In this report, we have utilized the crystal structure of the recombinant α(M) I domain to produce a three-dimensional model of the homologous region in the integrin β3 subunit. We performed mutagenesis of candidate amino acid residues predicted from this model to be involved in cation coordination and ligand binding. We report the identification of Asp127 and Glu220 as residues essential for the ligand binding function of α(IIb)β3. Alanine substitution of these residues did not affect receptor expression but abolished the binding of activation-dependent (PAC1) and -independent (OPG2) ligand mimetic antibodies. In our proposed model, β3 Asp217 is analogous to a metal- coordinating residue in the α(M) MIDAS domain, while Glu220 does not correspond to a functional MIDAS domain residue. Substitution of the highly conserved β3 residue Thr197 corresponding to a critical MIDAS metal- coordinating Thr residue did not affect ligand binding function, suggesting that this region of β3 adopts a structure that is very similar to but not identical to that of the MIDAS domain. These data support a functional linkage between these two sequences and further define a common feature of ligand binding to integrins.

Original languageEnglish (US)
Pages (from-to)21978-21984
Number of pages7
JournalJournal of Biological Chemistry
Volume271
Issue number36
DOIs
StatePublished - Sep 25 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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