title: Alterations in the intrinsic properties of the GPIbalpha-VWF tether bond define the kinetics of the platelet-type von Willebrand disease mutation, Gly233Val.
abstract: Platelet-type von Willebrand disease (PTVWD) is a bleeding disorder in which an increase of function mutation in glycoprotein Ibalpha (GPIbalpha), 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 GPIbalpha mutation, Gly233Val, 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 (k0 off values for mutant versus 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 wild-type (WT) receptor. Although the observed alterations in the intrinsic properties of the GPIbalpha-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 GPIbalpha-VWF-A1 interactions.
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8208, St Louis, MO 93110, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Doggett
authors.forename: Gaurav
authors.initials: G
authors.lastname: Girdhar
authors.forename: Avril
authors.initials: A
authors.lastname: Lawshe
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Miller
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Laurenzi
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Diacovo
mesh_terms: D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D020125:Mutation, Missense; D010477:Perfusion; D010973:Platelet Adhesiveness / Q000235:genetics; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D013314:Stress, Mechanical; D014842:von Willebrand Diseases / Q000235:genetics*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor