Monoclonal antibodies to ligand-occupied conformers of integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) alter receptor affinity, specificity, and function.
Occupancy of integrin receptors induces conformational changes in the receptor, resulting in exposure of novel interactive sites termed ligand-induced binding sites (LIBS). We report here that Fab fragments of certain antibodies against LIBS on integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa) block platelet aggregation. Thus, certain LIBS or the regions surrounding them may participate in events required for platelet aggregation. In addition, certain anti-alpha IIb beta 3 LIBS Fab fragments stimulated platelet aggregation. This was due to induction of fg binding to alpha IIb beta 3, apparently by shifting a conformational equilibrium between a "resting" and an "activated" state of alpha IIb beta 3. Some of the activating anti-LIBS Fab fragments also induced high affinity fibronectin binding to alpha IIb beta 3, whereas others did not. Thus, changes in the conformation of this integrin modulate both the specificity and affinity of ligand recognition.
Frelinger
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Research Institute of Scripps Clinic, La Jolla, California 92037.
Du
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Plow
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Ginsberg
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D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008024:Ligands; D008969:Molecular Sequence Data; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D005353:Fibronectins; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D010980:Platelet Membrane Glycoproteins; D013755:Tetradecanoylphorbol Acetate