Platelet-fibrinogen interactions.
Binding of fibrinogen to GPIIb-IIIa on agonist-stimulated platelets results in platelet aggregation, presumably by crosslinking adjacent activated platelets. Although unactivated platelets express numerous copies of GPIIb-IIIa on their surface, spontaneous, and potentially deleterious, platelet aggregation is prevented by tightly regulating the fibrinogen binding activity of GPIIb-IIIa. Preliminary evidence suggests that it is the submembranous actin or actin-associated proteins that constrains GPIIb-IIIa in a low affinity state and that relief of this constraint by initiating actin filament turnover enables GPIIb-IIIa to bind fibrinogen. Two regions of the fibrinogen alpha chain that contain an RGD motif, as well as the carboxyl-terminus of the fibrinogen gamma chain, represent potential binding sites for GPIIb-IIIa in the fibrinogen molecule. However, ultrastructural studies using purified fibrinogen and GPIIb-IIIa, and studies using recombinant fibrinogen in which the RGD and relevant gamma chain motifs were mutated indicate that sequences located at the carboxyl-terminal end of the gamma chain mediates fibrinogen binding to GPIIb-IIIa. There is evidence that fibrinogen itself binds to regions in the amino terminal portions of both GPIIb and GPIIIa and that the sites interacting with the fibrinogen gamma chain and with RGD-containing peptides are spatially distinct. Nonetheless, there appears to be allosteric linkage between these sites, accounting for the ability of RGD-containing peptides to inhibit platelet aggregation and arterial thrombosis.
Bennett
J S
JS
Hematology-Oncology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. bennetts@mail.med.upenn.edu
D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism*; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D009842:Oligopeptides / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011485:Protein Binding
D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen