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Calcium modulates force sensing by the von Willebrand factor A2 domain

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  • Arjen J. Jakobi

    (Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University)

  • Alireza Mashaghi

    (AMOLF Institute, Science Park 104)

  • Sander J. Tans

    (AMOLF Institute, Science Park 104)

  • Eric G. Huizinga

    (Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University)

Abstract

von Willebrand factor (VWF) multimers mediate primary adhesion and aggregation of platelets. VWF potency critically depends on multimer size, which is regulated by a feedback mechanism involving shear-induced unfolding of the VWF-A2 domain and cleavage by the metalloprotease ADAMTS-13. Here we report crystallographic and single-molecule optical tweezers data on VWF-A2 providing mechanistic insight into calcium-mediated stabilization of the native conformation that protects A2 from cleavage by ADAMTS-13. Unfolding of A2 requires higher forces when calcium is present and primarily proceeds through a mechanically stable intermediate with non-native calcium coordination. Calcium further accelerates refolding markedly, in particular, under applied load. We propose that calcium improves force sensing by allowing reversible force switching under physiologically relevant hydrodynamic conditions. Our data show for the first time the relevance of metal coordination for mechanical properties of a protein involved in mechanosensing.

Suggested Citation

  • Arjen J. Jakobi & Alireza Mashaghi & Sander J. Tans & Eric G. Huizinga, 2011. "Calcium modulates force sensing by the von Willebrand factor A2 domain," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1385
    DOI: 10.1038/ncomms1385
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    Cited by:

    1. Venkatraman Ramanujam & Hema Chandra Kotamarthi & Sri Rama Koti Ainavarapu, 2014. "Ca2+ Binding Enhanced Mechanical Stability of an Archaeal Crystallin," PLOS ONE, Public Library of Science, vol. 9(4), pages 1-9, April.

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