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Strong Binding of Platelet Integrin ?IIb?3 to Fibrin Clots: Potential Target to Destabilize Thrombi.

ABSTRACT: The formation of platelet thrombi is determined by the integrin ?IIb?3-mediated interactions of platelets with fibrinogen and fibrin. Blood clotting in vivo is catalyzed by thrombin, which simultaneously induces fibrinogen binding to ?IIb?3 and converts fibrinogen to fibrin. Thus, after a short time, thrombus formation is governed by ?IIb?3 binding to fibrin fibers. Surprisingly, there is little understanding of ?IIb?3 interaction with fibrin polymers. Here we used an optical trap-based system to measure the binding of single ?IIb?3 molecules to polymeric fibrin and compare it to ?IIb?3 binding to monomeric fibrin and fibrinogen. Like ?IIb?3 binding to fibrinogen and monomeric fibrin, we found that ?IIb?3 binding to polymeric fibrin can be segregated into two binding regimes, one with weaker rupture forces of 30-60?pN and a second with stronger rupture forces >60?pN that peaked at 70-80?pN. However, we found that the mechanical stability of the bimolecular ?IIb?3-ligand complexes had the following order: fibrin polymer?>?fibrin monomer?>?fibrinogen. These quantitative differences reflect the distinct specificity and underlying molecular mechanisms of ?IIb?3-mediated reactions, implying that targeting platelet interactions with fibrin could increase the therapeutic indices of antithrombotic agents by focusing on the destabilization of thrombi rather than the prevention of platelet aggregation.

SUBMITTER: Hook P

PROVIDER: S-EPMC5636895 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Strong Binding of Platelet Integrin αIIbβ3 to Fibrin Clots: Potential Target to Destabilize Thrombi.

Höök Peter P Litvinov Rustem I RI Kim Oleg V OV Xu Shixin S Xu Zhiliang Z Bennett Joel S JS Alber Mark S MS Weisel John W JW

Scientific reports 20171011 1

The formation of platelet thrombi is determined by the integrin αIIbβ3-mediated interactions of platelets with fibrinogen and fibrin. Blood clotting in vivo is catalyzed by thrombin, which simultaneously induces fibrinogen binding to αIIbβ3 and converts fibrinogen to fibrin. Thus, after a short time, thrombus formation is governed by αIIbβ3 binding to fibrin fibers. Surprisingly, there is little understanding of αIIbβ3 interaction with fibrin polymers. Here we used an optical trap-based system t ...[more]

PMID: 29021578

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Project description:The major platelet integrin, glycoprotein IIb-IIIa, binds soluble fibrinogen only after platelet activation. To investigate the mechanism by which platelets convert glycoprotein IIb-IIIa into a functional fibrinogen receptor, we characterized the opening and closing of fibrinogen-binding sites in isolated platelet membranes and compared the regulatory properties of membrane-bound glycoprotein IIb-IIIa with those of the detergent-solubilized receptor. Basal fibrinogen binding to the membranes possessed many of the properties of fibrinogen binding to activated platelets; however, less than 10% of glycoprotein IIb-IIIa in the membranes was capable of binding fibrinogen. Preincubating the membranes with either an activating glycoprotein IIb-IIIa antibody or alpha-chymotrypsin increased fibrinogen binding. In contrast, agents that require intracellular mediators, such as platelet agonists, guanine-nucleotide-binding-protein activators and purified protein kinase C, did not stimulate fibrinogen binding to the membranes, suggesting that cytosolic factor(s) may be required for activation of the receptor in platelets. Occupancy of glycoprotein IIb-IIIa in the membranes with RGD (Arg-Gly-Asp)-containing peptides reversibly exposed neoantigenic epitopes and fibrinogen-binding sites in the receptor. These conformational changes required membrane fixation to be maintained following peptide removal. Similar results were obtained with purified glycoprotein IIb-IIIa incorporated into phospholipid vesicles, indicating that the resting state of the receptor is favoured in these environments. In contrast, when the conformation of detergent-solubilized glycoprotein IIb-IIIa was altered by exposure to RGD-containing peptides, the receptor remained active even after incorporation into phospholipid vesicles. These results demonstrate that platelet membranes are a useful model in which to study the regulation of glycoprotein IIb-IIIa and suggest that the environment surrounding the receptor may have a profound influence on this process.

Dataset Information

Strong Binding of Platelet Integrin ?IIb?3 to Fibrin Clots: Potential Target to Destabilize Thrombi.

Publications

Strong Binding of Platelet Integrin αIIbβ3 to Fibrin Clots: Potential Target to Destabilize Thrombi.

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