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Mutual A domain interactions in the force sensing protein von Willebrand factor

The von Willebrand factor (VWF) is a glycoprotein in the blood that plays a central role in hemostasis. Among other functions, VWF is responsible for platelet adhesion at sites of injury via its A1 domain. Its adjacent VWF domain A2 exposes a cleavage site under shear to degrade long VWF fibers in o...

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Bibliographische Detailangaben
Hauptverfasser: Poschen, Sandra (VerfasserIn) , Aponte-Santamaria, Camilo (VerfasserIn) , Gräter, Frauke (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2017
In: Journal of structural biology
Year: 2017, Jahrgang: 197, Heft: 1, Pages: 57-64
ISSN:1095-8657
DOI:10.1016/j.jsb.2016.04.012
Online-Zugang:Verlag, Volltext: http://dx.doi.org/10.1016/j.jsb.2016.04.012
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S1047847716300818
Volltext
Verfasserangaben:Sandra Posch, Camilo Aponte-Santamaría, Richard Schwarzl, Andreas Karner, Matthias Radtke, Frauke Gräter, Tobias Obser, Gesa König, Maria A. Brehm, Hermann J. Gruber, Roland R. Netz, Carsten Baldauf, Reinhard Schneppenheim, Robert Tampé, Peter Hinterdorfer

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520 |a The von Willebrand factor (VWF) is a glycoprotein in the blood that plays a central role in hemostasis. Among other functions, VWF is responsible for platelet adhesion at sites of injury via its A1 domain. Its adjacent VWF domain A2 exposes a cleavage site under shear to degrade long VWF fibers in order to prevent thrombosis. Recently, it has been shown that VWF A1/A2 interactions inhibit the binding of platelets to VWF domain A1 in a force-dependent manner prior to A2 cleavage. However, whether and how this interaction also takes place in longer VWF fragments as well as the strength of this interaction in the light of typical elongation forces imposed by the shear flow of blood remained elusive. Here, we addressed these questions by using single molecule force spectroscopy (SMFS), Brownian dynamics (BD), and molecular dynamics (MD) simulations. Our SMFS measurements demonstrate that the A2 domain has the ability to bind not only to single A1 domains but also to VWF A1A2 fragments. SMFS experiments of a mutant [A2] domain, containing a disulfide bond which stabilizes the domain against unfolding, enhanced A1 binding. This observation suggests that the mutant adopts a more stable conformation for binding to A1. We found intermolecular A1/A2 interactions to be preferred over intramolecular A1/A2 interactions. Our data are also consistent with the existence of two cooperatively acting binding sites for A2 in the A1 domain. Our SMFS measurements revealed a slip-bond behavior for the A1/A2 interaction and their lifetimes were estimated for forces acting on VWF multimers at physiological shear rates using BD simulations. Complementary fitting of AFM rupture forces in the MD simulation range adequately reproduced the force response of the A1/A2 complex spanning a wide range of loading rates. In conclusion, we here characterized the auto-inhibitory mechanism of the intramolecular A1/A2 bond as a shear dependent safeguard of VWF, which prevents the interaction of VWF with platelets. 
650 4 |a Atomic force microscopy 
650 4 |a Brownian dynamics simulation 
650 4 |a Molecular dynamics simulation 
650 4 |a Primary hemostasis 
650 4 |a Single molecule force spectroscopy 
650 4 |a von Willebrand factor 
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