title: Expression of the phenotypic abnormality of platelet-type von Willebrand disease in a recombinant glycoprotein Ib alpha fragment.
abstract: The platelet GP Ib-IX receptor supports platelet adhesion and activation by binding to vWf in the exposed subendothelial matrix. An abnormal GP Ib-IX complex exists in platelet-type or pseudo-von Willebrand disease and has a characteristic increased affinity for soluble vWf resulting in impaired hemostatic function due to the removal of larger vWf multimers from the circulation. Genetic studies within an afflicted family have demonstrated that the disease is linked to a Gly233-->Val amino acid substitution within the alpha-subunit of the oligomeric GP Ib-IX complex (Miller, J.L., D. Cunningham, V.A. Lyle, and C. L. Finch. 1991. Proc. Natl. Acad. Sci. USA. 88:4761-4765). To evaluate the functional consequences of this mutation, we constructed a recombinant analogue of the alpha-subunit of GP Ib containing Val233. Experiments comparing molecules with either Gly233 or Val233 revealed that the Val substitution generates a molecule with increased affinity for vWf. The recombinant fragment reproduces the functional abnormality of the GP Ib-IX complex in platelet-type von Willebrand disease, thus establishing the molecular basis of the bleeding disorder within this family. Moreover, it becomes apparent that structural elements responsible for the regulation of hemostasis through modulation of vWf affinity for platelets reside within the alpha-subunit of the GP Ib-IX complex.
authors: Department of Molecular and Experimental Medicine/Committee on Vascular Biology, Roon Research Center for Arteriosclerosis and Thrombosis, Scripps Research Institute, La Jolla, California 92037.
authors: M
authors: M
authors: Murata
authors: S R
authors: SR
authors: Russell
authors: Z M
authors: ZM
authors: Ruggeri
authors: J
authors: J
authors: Ware
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003435:Crotalid Venoms / Q000494:pharmacology; D014644:Genetic Variation; D005998:Glycine; D006388:Hemagglutinins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D010641:Phenotype; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012310:Ristocetin / Q000494:pharmacology; D014162:Transfection; D014633:Valine; D014842:von Willebrand Diseases / Q000097:blood* / Q000235:genetics*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D003435:Crotalid Venoms; D006388:Hemagglutinins; D046911:Macromolecular Substances; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D012310:Ristocetin; C030961:botrocetin; D014633:Valine; D005998:Glycine