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Crucial role for the VWF A1 domain in binding to type IV collagen. Blood 2015 Apr 02;125(14):2297-304

Date

02/11/2015

Pubmed ID

25662333

Pubmed Central ID

PMC4383803

DOI

10.1182/blood-2014-11-610824

Scopus ID

2-s2.0-84926664083   61 Citations

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.

Author List

Flood VH, Schlauderaff AC, Haberichter SL, Slobodianuk TL, Jacobi PM, Bellissimo DB, Christopherson PA, Friedman KD, Gill JC, Hoffmann RG, Montgomery RR, Zimmerman Program Investigators

Authors

Veronica H. Flood MD Professor in the Pediatrics department at Medical College of Wisconsin
Kenneth D. Friedman MD Professor in the Medicine department at Medical College of Wisconsin
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Binding Sites
Case-Control Studies
Cells, Cultured
Collagen Type IV
Flow Cytometry
Humans
Mice
Mutagenesis, Site-Directed
Mutation
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Structure-Activity Relationship
von Willebrand Diseases
von Willebrand Factor