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

Posch, S., Aponte-Santamaría, C., Schwarzl, R., Karner, A., Radtke, M., Gräter, F., et al. (2017). Mutual A domain interactions in the force sensing protein von Willebrand factor. Journal of Structural Biology, 197(1), 57-64. doi:10.1016/j.jsb.2016.04.012.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-6CF8-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-B210-8
Genre: Journal Article

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1-s2.0-S1047847716300818-main.pdf (Publisher version), 2MB
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Copyright Date:
2016
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The Authors. Published by Elsevier Inc.

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 Creators:
Posch, Sandra1, Author
Aponte-Santamaría, Camilo 2, Author
Schwarzl, Richard 2, Author
Karner, Andreas 2, Author
Radtke, Matthias 3, Author
Gräter, Frauke 4, Author
Obser, Tobias 5, Author
König, Gesa 5, Author
Brehm, Maria A.5, Author
Gruber, Hermann J. 1, Author
Netz, Roland R3, Author
Baldauf, Carsten6, Author              
Schneppenheim, Reinhard 5, Author
Tampé, Robert7, Author
Hinterdorfer, Peter 1, 2, Author
Affiliations:
1Department of Applied Experimental Biophysics, Institute of Biophysics, Johannes Kepler University, Linz, Austria, escidoc:persistent22              
2Center for Advanced Bioanalysis GmbH (CBL), Linz, Austria, escidoc:persistent22              
3Department of Physics, FU Berlin, Berlin, Germany, escidoc:persistent22              
4Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany, escidoc:persistent22              
5Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, escidoc:persistent22              
6Theory, Fritz Haber Institute, Max Planck Society, escidoc:634547              
7Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt/Main, Germany, escidoc:persistent22              

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 Abstract: 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.

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 Dates: 2016-04-212016-01-282016-04-222016-04-232017-01
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.jsb.2016.04.012
 Degree: -

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Title: Journal of Structural Biology
  Abbreviation : J. Struct. Biol.
Source Genre: Journal
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Publ. Info: Orlando, Fla. : Academic Press
Pages: 8 Volume / Issue: 197 (1) Sequence Number: - Start / End Page: 57 - 64 Identifier: ISSN: 1047-8477
CoNE: http://pubman.mpdl.mpg.de/cone/journals/resource/954922650160