Document Detail

Shear stress-induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region.
MedLine Citation:
PMID:  21917758     Owner:  NLM     Status:  MEDLINE    
VWF is required for platelet adhesion to sites of vessel injury, a process vital for both hemostasis and thrombosis. Enhanced VWF secretion and oxidative stress are both hallmarks of inflammation. We recently showed that the neutrophil oxidant hypochlorous acid (HOCl) inhibits VWF proteolysis by ADAMTS13 by oxidizing VWF methionine 1606 (M1606) in the A2 domain. M1606 was readily oxidized in a substrate peptide, but required urea in multimeric plasma VWF. In the present study, we examined whether shear stress enhances VWF oxidation. With an HOCl-generating system containing myeloperoxidase (MPO) and H(2)O(2), we found that shear stress accelerated M1606 oxidation, with 56% becoming oxidized within 1 hour. Seven other methionine residues in the VWF A1A2A3 region (containing the sites for platelet and collagen binding and ADAMTS13 cleavage) were variably oxidized, one completely. Oxidized methionines accumulated preferentially in the largest VWF multimers. HOCl-oxidized VWF was hyperfunctional, agglutinating platelets at ristocetin concentrations that induced minimal agglutination using unoxidized VWF and binding more of the nanobody AU/VWFa-11, which detects a gain-of-function conformation of the A1 domain. These findings suggest that neutrophil oxidants will both render newly secreted VWF uncleavable and alter the largest plasma VWF forms such that they become hyperfunctional and resistant to proteolysis by ADAMTS13.
Xiaoyun Fu; Junmei Chen; Ryan Gallagher; Ying Zheng; Dominic W Chung; José A López
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-13
Journal Detail:
Title:  Blood     Volume:  118     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-14     Completed Date:  2012-01-03     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5283-91     Citation Subset:  AIM; IM    
Research Division, Puget Sound Blood Center, Seattle, WA 98104, USA.
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MeSH Terms
ADAM Proteins / metabolism
Binding Sites
Blood Platelets / metabolism
Hypochlorous Acid
Methionine / chemistry
Models, Molecular
Protein Multimerization
Protein Unfolding
Shear Strength
Stress, Mechanical
von Willebrand Factor / chemistry*,  metabolism
Grant Support
Reg. No./Substance:
0/von Willebrand Factor; 63-68-3/Methionine; 7790-92-3/Hypochlorous Acid; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/ADAMTS13 protein, human
Comment In:
Blood. 2011 Nov 10;118(19):5068-9   [PMID:  22077073 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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