title: A new model of dual interacting ligand binding sites on integrin alphaIIbbeta3.
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.
authors.affiliation: Program on Cell Adhesion, Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Hu
authors.forename: C A
authors.initials: CA
authors.lastname: White
authors.forename: S
authors.initials: S
authors.lastname: Panzer-Knodle
authors.forename: J D
authors.initials: JD
authors.lastname: Page
authors.forename: N
authors.initials: N
authors.lastname: Nicholson
authors.forename: J W
authors.initials: JW
authors.lastname: Smith
mesh_terms: D000494:Allosteric Regulation; D001667:Binding, Competitive; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009842:Oligopeptides / Q000378:metabolism; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D020349:Surface Plasmon Resonance