Lateral self-association of VWF involves the Cys2431-Cys2453 disulfide/dithiol in the C2 domain

Ganderton, Tim, Wong, Jason W. H., Schroeder, Christina and Hogg, Philip J. (2011) Lateral self-association of VWF involves the Cys2431-Cys2453 disulfide/dithiol in the C2 domain. Blood, 118 19: 5312-5318. doi:10.1182/blood-2011-06-360297


Author Ganderton, Tim
Wong, Jason W. H.
Schroeder, Christina
Hogg, Philip J.
Title Lateral self-association of VWF involves the Cys2431-Cys2453 disulfide/dithiol in the C2 domain
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2011-11-01
Sub-type Article (original research)
DOI 10.1182/blood-2011-06-360297
Open Access Status Not yet assessed
Volume 118
Issue 19
Start page 5312
End page 5318
Total pages 7
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
Abstract VWF is a plasma protein that binds platelets to an injured vascular wall during thrombosis. When exposed to the shear forces found in flowing blood, VWF molecules undergo lateral self-association that results in a meshwork of VWF fibers. Fiber formation has been shown to involve thiol/disulfide exchange between VWF molecules. A C-terminal fragment of VWF was expressed in mammalian cells and examined for unpaired cysteine thiols using tandem mass spectrometry (MS). The VWF C2 domain Cys2431-Cys2453 disulfide bond was shown to be reduced in approximately 75% of the molecules. Fragments containing all 3 C domains or just the C2 domain formed monomers, dimers, and higher-order oligomers when expressed in mammalian cells. Mutagenesis studies showed that both the Cys2431-Cys2453 and nearby Cys2451-Cys2468 disulfide bonds were involved in oligomer formation. Our present findings imply that lateral VWF dimers form when a Cys2431 thiolate anion attacks the Cys2431 sulfur atom of the Cys2431-Cys2453 disulfide bond of another VWF molecule, whereas the Cys2451-Cys2468 disulfide/dithiol mediates formation of trimers and higher-order oligomers. These observations provide the basis for exploring defects in lateral VWF association in patients with unexplained hemorrhage or thrombosis.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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