|
|
Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2003-01-0072.
Submitted January 9, 2003
Accepted February 27, 2003
Alterations in the intrinsic properties of the GPIb alpha - vWF tether bond define the kinetics of the platelet-type von Willebrand disease mutation, G233V
Teresa A Doggett, Gaurav Girdhar, Avril Lawshe, Jonathan L Miller, Ian J Laurenzi, Scott L Diamond, and Thomas G Diacovo*
Departments of Pediatrics and Pathology, Washington University and St. Louis Children's Hospital, St. Louis, MO, USA
Department of Pathology, University of Chicago, Chicago, IL, USA
Department of Chemical Engineering, University of Pennsylvania, Philadelphia, PA, USA
* Corresponding author; email: diacovo_t{at}kids.wustl.edu.
Platelet type von Willebrand disease (PT-vWD) is a bleeding disorder in which an increase of function mutation in glycoprotein Ib alpha (GPIb alpha), with respect to binding of von Willebrand factor (vWF), results in a loss of circulating high molecular weight vWF multimers together with a mild-moderate thrombocytopenia. To better ascertain the specific perturbations in adhesion associated with this disease state, we performed a detailed analysis of the kinetic and mechanical properties of tether bonds formed between PT-vWD platelets and the A1-domain of vWF. Results indicate that the GPIb alpha mutation, G233V promotes and stabilizes platelet adhesion to vWF at shear rates that do not support binding between the native receptor-ligand pair due to enhanced formation and increased longevity of the mutant tether bond (koff0 values for mutant vs. native complex of 0.67 ± 0.11 s-1 and 3.45 ± 0.37 s-1, respectively). By contrast, the sensitivity of this interaction to an applied force, a measure of bond strength, was similar to the WT receptor. Although the observed alteration in the intrinsic properties of the GPIb alpha - vWF tether bond are comparable to those reported for the type 2B vWD, distinct molecular mechanisms may be responsible for these function-enhancing bleeding disorders as interactions between the mutant receptor and mutant ligand resulted in a greater stability in platelet adhesion. We speculate that the enhanced cellular on-rate together with the prolongation in the lifetime of the mutant receptor-ligand bond contributes to platelet aggregation in circulating blood by permitting the formation of multiple GPIb alpha - vWF-A1 interactions.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. Tauxe, X. Xie, M. Joffraud, M. Martinez, M. Schapira, and O. Spertini
P-selectin Glycoprotein Ligand-1 Decameric Repeats Regulate Selectin-dependent Rolling under Flow Conditions
J. Biol. Chem.,
October 17, 2008;
283(42):
28536 - 28545.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lou and C. Zhu
Flow induces loop-to-{beta}-hairpin transition on the {beta}-switch of platelet glycoprotein Ib{alpha}
PNAS,
September 16, 2008;
105(37):
13847 - 13852.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lou, T. Yago, A. G. Klopocki, P. Mehta, W. Chen, V. I. Zarnitsyna, N. V. Bovin, C. Zhu, and R. P. McEver
Flow-enhanced adhesion regulated by a selectin interdomain hinge
J. Cell Biol.,
September 25, 2006;
174(7):
1107 - 1117.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Dumas, R. Kumar, T. McDonagh, F. Sullivan, M. L. Stahl, W. S. Somers, and L. Mosyak
Crystal Structure of the Wild-type von Willebrand Factor A1-Glycoprotein Ib{alpha} Complex Reveals Conformation Differences with a Complex Bearing von Willebrand Disease Mutations
J. Biol. Chem.,
May 28, 2004;
279(22):
23327 - 23334.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
