title: Crucial role for the VWF A1 domain in binding to type IV collagen.
abstract: Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis.
authors: Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI;
authors: Veronica H
authors: VH
authors: Flood
authors: Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Abraham C
authors: AC
authors: Schlauderaff
authors: Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Sandra L
authors: SL
authors: Haberichter
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Tricia L
authors: TL
authors: Slobodianuk
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Paula M
authors: PM
authors: Jacobi
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Daniel B
authors: DB
authors: Bellissimo
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Pamela A
authors: PA
authors: Christopherson
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Kenneth D
authors: KD
authors: Friedman
authors: Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Joan Cox
authors: JC
authors: Gill
authors: Department of Pediatrics, Division of Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI.
authors: Raymond G
authors: RG
authors: Hoffmann
authors: Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.
authors: Robert R
authors: RR
authors: Montgomery
mesh_terms: D000818:Animals; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014842:von Willebrand Diseases / Q000235:genetics / Q000378:metabolism*; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D024141:Collagen Type IV; D014841:von Willebrand Factor