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* Department of Bioengineering and Department of Chemistry, Rice University, Houston, Texas; and Division of Thrombosis Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
Correspondence: Address reprint requests to Bahman Anvari, Dept. of Bioengineering, MS-142, Rice University, PO Box 1892, Houston, TX 77251. Tel.: 713-348-5870; Fax: 713-348-5877; E-mail: anvari{at}rice.edu.
The first stage in hemostasis is the binding of the platelet membrane receptor glycoprotein (GP) Ib-IX complex to the A1 domain of von Willebrand factor in the subendothelium. A bleeding disorder associated with this interaction is platelet-type von Willebrand disease, which results from gain-of-function (GOF) mutations in amino acid residues 233 or 239 of the GP Ib
subunit of GP Ib-IX. Using optical tweezers and a quadrant photodetector, we investigated the binding of A1 to GOF and loss-of-function mutants of GP Ib with mutations in the region containing the two known naturally occurring mutations. By dynamically measuring unbinding force profiles at loading rates ranging from 200–20,000 pN/s, we found that the bond strengths between A1 and GP Ib GOF mutants (233, 235, 237, and 239) were significantly greater than the A1/wild-type GP Ib-IX bond at all loading rates examined (p < 0.05). In addition, mutants 231 and 232 exhibited significantly lower bond strengths with A1 than the wild-type receptors (p < 0.05). We computed unloaded dissociation rate constant (
) values for interactions involving mutant and wild-type GP Ib-IX receptors with A1 and found the A1/wild-type GP Ib-IX value of 5.47 ± 0.25 s–1 to be significantly greater than the GOF values and significantly less than the loss-of-function values. Our data illustrate the importance of the bond kinetics associated with the VWF/GP Ib-IX interaction in hemostasis and also demonstrate the drastic changes in binding that can occur when only a single amino acid of GP Ib is altered.
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