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: Veronica H Flood, Abraham C Schlauderaff, Sandra L Haberichter, Tricia L Slobodianuk, Paula M Jacobi, Daniel B Bellissimo, Pamela A Christopherson, Kenneth D Friedman, Joan Cox Gill, Raymond G Hoffmann, Robert R Montgomery, Zimmerman Program Investigators
• Journal: Blood (Blood) Vol. 125 Issue 14 Pg. 2297-304 (Apr 02 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25662333 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Collagen Type IV
• von Willebrand Factor

Topics

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