A new model of dual interacting ligand binding sites on integrin α(IIb)β3

Abstract

The platelet integrin α(IIb)β3 mediates platelet aggregation and platelet adhesion. This integrin is the key to hemostasis and also to pathologic vascular occlusion. A key domain on α(IIb)β3 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 α(IIb)β3 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 α(IIb)β3 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 α(IIb)β3 even when it is already occupied by fibrinogen. Once bound, RGD-type ligands induce the dissociation of fibrinogen from α(IIb)β3. This allosteric cross-talk has important implications for anti-platelet therapy because it suggests a novel approach for the dissolution of existing platelet thrombi.