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- Publisher Website: 10.1182/blood-2011-06-360297
- Scopus: eid_2-s2.0-81155151848
- PMID: 21911836
- WOS: WOS:000296867100034
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Article: Lateral self-association of VWF involves the Cys2431-Cys2453 disulfide/dithiol in the C2 domain
Title | Lateral self-association of VWF involves the Cys2431-Cys2453 disulfide/dithiol in the C2 domain |
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Authors | |
Issue Date | 2011 |
Citation | Blood, 2011, v. 118, n. 19, p. 5312-5318 How to Cite? |
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. © 2011 by The American Society of Hematology. |
Persistent Identifier | http://hdl.handle.net/10722/250978 |
ISSN | 2023 Impact Factor: 21.0 2023 SCImago Journal Rankings: 5.272 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Ganderton, Tim | - |
dc.contributor.author | Wong, Jason W H | - |
dc.contributor.author | Schroeder, Christina | - |
dc.contributor.author | Hogg, Philip J. | - |
dc.date.accessioned | 2018-02-01T01:54:14Z | - |
dc.date.available | 2018-02-01T01:54:14Z | - |
dc.date.issued | 2011 | - |
dc.identifier.citation | Blood, 2011, v. 118, n. 19, p. 5312-5318 | - |
dc.identifier.issn | 0006-4971 | - |
dc.identifier.uri | http://hdl.handle.net/10722/250978 | - |
dc.description.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. © 2011 by The American Society of Hematology. | - |
dc.language | eng | - |
dc.relation.ispartof | Blood | - |
dc.title | Lateral self-association of VWF involves the Cys2431-Cys2453 disulfide/dithiol in the C2 domain | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1182/blood-2011-06-360297 | - |
dc.identifier.pmid | 21911836 | - |
dc.identifier.scopus | eid_2-s2.0-81155151848 | - |
dc.identifier.volume | 118 | - |
dc.identifier.issue | 19 | - |
dc.identifier.spage | 5312 | - |
dc.identifier.epage | 5318 | - |
dc.identifier.eissn | 1528-0020 | - |
dc.identifier.isi | WOS:000296867100034 | - |
dc.identifier.issnl | 0006-4971 | - |