Thromb Haemost 2003; 90(05): 853-862
DOI: 10.1160/TH03-03-0157
Platelets and Blood Cells
Schattauer GmbH

A mutation in the integrin αIIb subunit that selectively inhibits αIIbβ3 receptor function

Kim B. Perkins
1   Mayo Clinic Scottsdale, Scottsdale, Arizona, USA
,
Joseph C. Loftus
1   Mayo Clinic Scottsdale, Scottsdale, Arizona, USA
› Institutsangaben
Financial support: This work was supported in part by National Institutes of Health Grants F32 HL10493 (K.B.P.) and HL67938 (J.C.L.).
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Publikationsverlauf

Received 17. März 2003

Accepted after revision 18. Juli 2003

Publikationsdatum:
05. Dezember 2017 (online)

Summary

The αIIband αvintegrins have been shown to play a significant role in a variety of disease processes. αIIbβ3is a platelet-specific fibrinogen receptor that is critical for thrombosis and hemo-stasis. Determination of the basis of ligand recognition by αIIbβ3is essential for modulation of platelet function. To identify αIIbresidues involved in αIIbβ3ligand binding function, cells expressing a constitutively active variant of αIIbβ3were randomly mutagenized and selected for loss of αIIbβ3ligand binding function. One mutant isolated in this manner contained a single amino acid substitution at position 96 in αIIb(Ser96→Leu). Cells expressing this αIIbmutant did not bind the ligand mimetic antibody PAC1 or adhere to fibrinogen. In addition, the mutant receptor did not bind to an RGD affinity matrix. Substitution of conserved serine residues at position 1 in β strand A of all seven repeats of αIIbsimilarly inhibited ligand binding to αIIbβ3. αIIbS96 maps to the central cavity of the β–propeller fold of the αIIbsubunit immediately adjacent to a structurally important sequence at the center of the α and β subunit interface. In contrast, substitution of the analogous residues in αvor α4did not disrupt the ligand binding function of αvβ3or α4β1. These data support a potential unique structural or mechanistic role for this residue in αIIbβ3receptor function.

 
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