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Kim B. Perkins, Joseph C. Loftus
A mutation in the integrin IIb subunit that selectively inhibits IIb3 receptor function
The IIb and v integrins have been shown to play a significant role in a variety of disease processes. IIb3 is a platelet-specific fibrinogen receptor that is critical for thrombosis and hemostasis. Determination of the basis of ligand recognition by IIb3 is essential for modulation of platelet function. To identify IIb residues involved in IIb3 ligand binding function, cells expressing a constitutively active variant of IIb3 were randomly mutagenized and selected for loss of IIb3 ligand binding function. One mutant isolated in this manner contained a single amino acid substitution at position 96 in IIb (Ser9Leu). Cells expressing this IIb mutant 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 strand A of all seven repeats of IIb similarly inhibited ligand binding to IIb3. IIbS96 maps to the central cavity of the -propeller fold of the IIb subunit immediately adjacent to a structurally important sequence at the center of the and subunit interface. In contrast, substitution of the analogous residues in v or 4 did not disrupt the ligand binding function of v3 or 41. These data support a potential unique structural or mechanistic role for this residue in IIb3 receptor function.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 90, 11/2003
Pages: 853 - 862