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J Biol Chem, Vol. 274, Issue 8, 4633-4639, February 19, 1999

A New Model of Dual Interacting Ligand Binding Sites on Integrin alpha IIbbeta 3

Dana D. HuDagger , Carol A. WhiteDagger , Susan Panzer-Knodle, James D. Page, Nancy Nicholson, and Jeffrey W. SmithDagger

From the Dagger  Program on Cell Adhesion, Cancer Research Center, The Burnham Institute, La Jolla, California 92037 and the  Department of Cardiovascular Disease Research, Searle, Skokie, Illinois 60077

The platelet integrin alpha IIbbeta 3 mediates platelet aggregation and platelet adhesion. This integrin is the key to hemostasis and also to pathologic vascular occlusion. A key domain on alpha IIbbeta 3 is the ligand binding site, which can bind to plasma fibrinogen and to a number of Arg-Gly-Asp (RGD)-type ligands. However, the nature and function of the ligand binding pocket on alpha IIbbeta 3 remains controversial. Some studies suggest the presence of two ligand binding pockets, whereas other reports indicate a single binding pocket. Here we use surface plasmon resonance to show that alpha IIbbeta 3 contains two distinct ligand binding pockets. One site binds to fibrinogen, and a separate site binds to RGD-type ligands. More importantly, however, the two ligand binding pockets are interactive. RGD-type ligands are capable of binding to alpha IIbbeta 3 even when it is already occupied by fibrinogen. Once bound, RGD-type ligands induce the dissociation of fibrinogen from alpha IIbbeta 3. This allosteric cross-talk has important implications for anti-platelet therapy because it suggests a novel approach for the dissolution of existing platelet thrombi.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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