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Title: pH-Dependent Interactions in Dimers Govern the Mechanics and Structure of von Willebrand Factor
Authors: Müller, Jochen P ×
Löf, Achim
Mielke, Salomé
Obser, Tobias
Bruetzel, Linda K
Vanderlinden, Willem
Lipfert, Jan
Schneppenheim, Reinhard
Benoit, Martin #
Issue Date: Jul-2016
Publisher: Biophysical Society
Series Title: Biophysical Journal vol:111 issue:2
Article number: 10.1016/j.bpj.2016.06.022
Abstract: Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that is activated for hemostasis by increased hydrodynamic forces at sites of vascular injury. Here, we present data from atomic force microscopy-based single-molecule force measurements, atomic force microscopy imaging, and small-angle x-ray scattering to show that the structure and mechanics of VWF are governed by multiple pH-dependent interactions with opposite trends within dimeric subunits. In particular, the recently discovered strong intermonomer interaction, which induces a firmly closed conformation of dimers and crucially involves the D4 domain, was observed with highest frequency at pH 7.4, but was essentially absent at pH values below 6.8. However, below pH 6.8, the ratio of compact dimers increased with decreasing pH, in line with a previous transmission electron microscopy study. These findings indicated that the compactness of dimers at pH values below 6.8 is promoted by other interactions that possess low mechanical resistance compared with the strong intermonomer interaction. By investigating deletion constructs, we found that compactness under acidic conditions is primarily mediated by the D4 domain, i.e., remarkably by the same domain that also mediates the strong intermonomer interaction. As our data suggest that VWF has the highest mechanical resistance at physiological pH, local deviations from physiological pH (e.g., at sites of vascular injury) may represent a means to enhance VWF's hemostatic activity where needed.
URI: 
ISSN: 0006-3495
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

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