A New Model of Dual Interacting Ligand Binding Sites on Integrin αIIbβ3

Abstract

The platelet integrin alphaIIbbeta3 mediates platelet aggregation and platelet adhesion. This integrin is the key to hemostasis and also to pathologic vascular occlusion. A key domain on alphaIIbbeta3 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 alphaIIbbeta3 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 alphaIIbbeta3 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 alphaIIbbeta3 even when it is already occupied by fibrinogen. Once bound, RGD-type ligands induce the dissociation of fibrinogen from alphaIIbbeta3. This allosteric cross-talk has important implications for anti-platelet therapy because it suggests a novel approach for the dissolution of existing platelet thrombi.