A mutation in the integrin alphaIIb subunit that selectively inhibits alphaIIb beta3 receptor function.
The alpha(IIb) and alpha(v) integrins have been shown to play a significant role in a variety of disease processes. alpha(IIb)beta(3) is a platelet-specific fibrinogen receptor that is critical for thrombosis and hemostasis. Determination of the basis of ligand recognition by alpha(IIb)beta(3) is essential for modulation of platelet function. To identify alpha(IIb) residues involved in alpha(IIb)beta(3) ligand binding function, cells expressing a constitutively active variant of alpha(IIb)beta(3) were randomly mutagenized and selected for loss of alpha(IIb)beta(3) ligand binding function. One mutant isolated in this manner contained a single amino acid substitution at position 96 in alpha(IIb) (Ser9-->Leu). Cells expressing this alpha(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 beta strand A of all seven repeats of alpha(IIb) similarly inhibited ligand binding to alpha(IIb)beta(3). alpha(IIb)S96 maps to the central cavity of the beta-propeller fold of the alpha(IIb) subunit immediately adjacent to a structurally important sequence at the center of the alphaand beta subunit interface. In contrast, substitution of the analogous residues in alpha(v) or alpha(4) did not disrupt the ligand binding function of alpha(v)beta(3) or alpha(4)beta(1). These data support a potential unique structural or mechanistic role for this residue in alpha(IIb)beta(3) receptor function.
Mayo Clinic Scottsdale, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259, USA.
Kim B
KB
Perkins
Joseph C
JC
Loftus
D019943:Amino Acid Substitution; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009842:Oligopeptides / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics* / Q000502:physiology; D017354:Point Mutation / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D012694:Serine; D014162:Transfection
D008024:Ligands; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D040201:Platelet Membrane Glycoprotein IIb; D012694:Serine; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen