title: von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib.
abstract: von Willebrand factor (vWF) is a multimeric glycoprotein that mediates the adhesion of platelets to the subendothelium by binding to platelet glycoprotein Ib. For human vWF, this interaction can be induced in vitro by the antibiotic ristocetin or the snake venom protein botrocetin. A missense mutation, Gly-561-->Ser, was identified within the proposed glycoprotein Ib binding domain of vWF in the proband with von Willebrand disease type B, a unique variant characterized by no ristocetin-induced, but normal botrocetin-induced, binding to glycoprotein Ib. The corresponding mutant recombinant protein, rvWF(G561S), formed normal multimers and exhibited the same functional defect as the patient's plasma vWF, confirming that this mutation causes von Willebrand disease type B. These data show that botrocetin and ristocetin cofactor activities of vWF can be dissociated by a point mutation and confirm that these mediators promote vWF binding to platelets by different mechanisms. The normal botrocetin-induced binding and the defective ristocetin-induced binding of rvWF(G561S) suggest that the primary defect in von Willebrand disease type B may be a failure of normal allosteric regulation of the glycoprotein Ib binding function of vWF.
authors.affiliation: Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO.
authors.forename: I
authors.initials: I
authors.lastname: Rabinowitz
authors.forename: E A
authors.initials: EA
authors.lastname: Tuley
authors.forename: D J
authors.initials: DJ
authors.lastname: Mancuso
authors.forename: A M
authors.initials: AM
authors.lastname: Randi
authors.forename: B G
authors.initials: BG
authors.lastname: Firkin
authors.forename: M A
authors.initials: MA
authors.lastname: Howard
authors.forename: J E
authors.initials: JE
authors.lastname: Sadler
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003435:Crotalid Venoms / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D012310:Ristocetin / Q000378:metabolism; D014842:von Willebrand Diseases / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D003435:Crotalid Venoms; D009838:Oligodeoxyribonucleotides; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D012310:Ristocetin; C030961:botrocetin