title: Defect of heparin binding in plasma and recombinant von Willebrand factor with type 2 von Willebrand disease mutations.
abstract: The aim of our study was to characterise heparin-binding properties of mutated von Willebrand factor (VWF) in 24 patients plasmas with type 2 von Willebrand disease (VWD). and in 15 recombinant VWF (rVWF) with the corresponding mutations. Binding of mutated rVWF or plasma VWF was compared to that of WT-rVWF or normal pool plasma VWF. Four mutations, at positions C509, V551, R552 and R611 lead to significantly decreased binding to heparin in both plasma and rVWF. Interestingly, whereas these four residues are distant in the primary structure of VWF-A1domain, they are close to each other in its three-dimensional structure. Structural analysis suggested how folding problems and destabilisation due to these mutations could induce reorganisation of surface regions involved in heparin binding. In contrast, no heparin-binding defect was found associated with different type 2 VWF mutants, at positions G561, E596, I662, R543, R545, V553, R578 or L697.
authors.affiliation: INSERM U143, Bicetre, France.
authors.forename: G
authors.initials: G
authors.lastname: Rastegar-Lari
authors.forename: N
authors.initials: N
authors.lastname: Ajzenberg
authors.forename: A S
authors.initials: AS
authors.lastname: Ribba
authors.forename: V
authors.initials: V
authors.lastname: Vereycken-Holler
authors.forename: P
authors.initials: P
authors.lastname: Legendre
authors.forename: B
authors.initials: B
authors.lastname: Villoutreix
authors.forename: D
authors.initials: D
authors.lastname: Meyer
authors.forename: D
authors.initials: D
authors.lastname: Baruch
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D003062:Codon / Q000235:genetics; D003553:Cystine / Q000737:chemistry; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D020125:Mutation, Missense; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D025941:Protein Interaction Mapping; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012310:Ristocetin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014162:Transfection; D014842:von Willebrand Diseases / Q000097:blood* / Q000235:genetics; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D003062:Codon; D019038:Platelet Glycoprotein GPIb-IX Complex; D011993:Recombinant Fusion Proteins; D014841:von Willebrand Factor; D012310:Ristocetin; D003553:Cystine; D006493:Heparin