Crucial role for the VWF A1 domain in binding to type IV collagen

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

doi:10.1182/blood-2014-11-610824

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Crucial role for the VWF A1 domain in binding to type IV collagen

Journal article

Open access

Peer reviewed

Crucial role for the VWF A1 domain in binding to type IV collagen

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, …

Blood, Vol.125(14), pp.2297-2304

04/02/2015

DOI: 10.1182/blood-2014-11-610824

PMCID: PMC4383803

PMID: 25662333

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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.

Flow Cytometry

Animals

Binding Sites

Case-Control Studies

Cells, Cultured

Collagen Type IV - metabolism

Humans

Mice

Mutagenesis, Site-Directed

Mutation - genetics

Protein Binding

Protein Conformation

Protein Structure, Tertiary

Structure-Activity Relationship

von Willebrand Diseases - genetics

von Willebrand Diseases - metabolism

von Willebrand Factor - chemistry

von Willebrand Factor - genetics

von Willebrand Factor - metabolism

Details

Title: Subtitle: Crucial role for the VWF A1 domain in binding to type IV collagen
Creators: Veronica H Flood - Children's Hospital of Wisconsin
Abraham C Schlauderaff - Children's Hospital of Wisconsin
Sandra L Haberichter - Children's Hospital of Wisconsin
Tricia L Slobodianuk
Paula M Jacobi
Daniel B Bellissimo
Pamela A Christopherson
Kenneth D Friedman
Joan Cox Gill - Children's Hospital of Wisconsin
Raymond G Hoffmann - Medical College of Wisconsin
Robert R Montgomery - Children's Hospital of Wisconsin
Zimmerman Program Investigators
Contributors: A Sharathkumar (Contributor) - University of Iowa, Hematology/Oncology
Resource Type: Journal article
Publication Details: Blood, Vol.125(14), pp.2297-2304
DOI: 10.1182/blood-2014-11-610824
PMID: 25662333
PMCID: PMC4383803
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: R01 HL033721 / NHLBI NIH HHS HL081588 / NHLBI NIH HHS K08HL102260 / NHLBI NIH HHS K08 HL102260 / NHLBI NIH HHS P01 HL044612 / NHLBI NIH HHS T35 HL072483 / NHLBI NIH HHS P01 HL081588 / NHLBI NIH HHS HL33721 / NHLBI NIH HHS HL044612 / NHLBI NIH HHS
Language: English
Date published: 04/02/2015
Academic Unit: Stead Family Department of Pediatrics; Hematology/Oncology
Record Identifier: 9984353839602771

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