{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:28:33Z","timestamp":1787909313152,"version":"build-2784847793"},"reference-count":41,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>von Willebrand factor (VWF) self-association results in the homotypic binding of VWF upon exposure to fluid shear. The molecular mechanism of this process is not established. In this study, we demonstrate that the shear-dependent unfolding of the VWF A2 domain in the multimeric protein is a major regulator of protein self-association. This mechanism controls self-association on the platelet glycoprotein Ib\u03b1 receptor, on collagen substrates, and during thrombus growth ex vivo. In support of this, A2-domain mutations that prevent domain unfolding due to disulfide bridging of N- and C-terminal residues (\u201cLock-VWF\u201d) reduce self-association and platelet activation under various experimental conditions. In contrast, reducing assay calcium concentrations, and 2 mutations that destabilize VWF-A2 conformation by preventing coordination with calcium (D1498A and R1597W VWD type 2A mutation), enhance self-association. Studies using a panel of recombinant proteins that lack the A1 domain (\u201c\u0394A1 proteins\u201d) suggest that besides pure homotypic A2 interactions, VWF-A2 may also engage other protein domains to control self-association. Addition of purified high-density lipoprotein and apolipoprotein-A1 partially blocked VWF self-association. Overall, similar conditions facilitate VWF self-association and ADAMTS13-mediated proteolysis, with low calcium and A2 disease mutations enhancing both processes, and locking-A2 blocking them simultaneously. Thus, VWF appears to have evolved 2 balancing molecular functions in a single A2 functional domain to dynamically regulate protein size in circulation: ADAMTS13-mediated proteolysis and VWF self-association. Modulating self-association rates by targeting VWF-A2 may provide novel methods to regulate the rates of thrombosis and hemostasis.<\/jats:p>","DOI":"10.1182\/bloodadvances.2018030122","type":"journal-article","created":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T20:45:34Z","timestamp":1554151534000},"page":"957-968","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":40,"title":["von Willebrand factor self-association is regulated by the shear-dependent unfolding of the A2 domain"],"prefix":"10.1182","volume":"3","author":[{"given":"Changjie","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering and"},{"name":"Department of Medicine, University at Buffalo, State University of New York, Buffalo, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anju","family":"Kelkar","sequence":"additional","affiliation":[{"name":"Department of Chemical and 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