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-vWF-A1 Tether Bond under Flow: Effect of GPIb Mutations on the Association and Dissociation Rates
* Department of Bioengineering, Rice University, Houston, Texas; and Thrombosis Research Section, Department of Medicine, Baylor College of Medicine, Houston, Texas
Correspondence: Address reprint requests to Larry V. McIntire, PhD, Department of Biomedical Engineering, Georgia Tech and Emory University, 313 Ferst Drive, Suite 2116, Atlanta, Georgia 30332-0535. Tel.: 404-894-5057; Fax: 404-385-5028; E-mail: larry.mcintire{at}bme.gatech.edu.
The interaction between platelet glycoprotein (GP) Ib-IX-V complex and von Willebrand factor (vWF) is the first step of the hemostatic response to vessel injury. In platelet-type von Willebrand disease, two mutations, G233V and M239V, have been described within the Cys209-Cys248 disulfide loop of GPIb
that compromise hemostasis by increasing the affinity for vWF. We have earlier shown that converting other residues in this region to valine alters the affinity of GPIb for vWF, with mutations K237V and Q232V, respectively, showing the greatest increase and decrease in affinity. Here, we investigated further the effect of these two mutations on the kinetics of the GPIb interaction with the vWF-A1 domain under dynamic flow conditions. We measured the cellular on- and off-rate constants of Chinese hamster ovary cells expressing GPIb-IX complexes containing wild-type or mutant GPIb interacting with vWF-A1-coated surfaces at different shear stresses. We found that the gain-of-function mutant, K237V, rolled very slowly and continuously on vWF-A1 surface while the loss-of-function mutant, Q232V, showed fast, saltatory movement compared to the wild-type (WT). The off-rate constants, calculated based on the analysis of lifetimes of transient tethers formed on surfaces coated with limiting densities of vWF-A1, revealed that the Q232V and K237V dissociated 1.25-fold faster and 2.2-fold slower than the WT. The cellular on-rate constant of WT, measured in terms of tethering frequency, was threefold more and threefold less than Q232V and K237V, respectively. Thus, the gain- and loss-of-function mutations in GPIb affect both the association and dissociation kinetics of the GPIb-vWF-A1 bond. These findings are in contrast to the functionally similar selectin bonds where some of the mutations have been reported to affect only the dissociation rate.
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