Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 23, Pages 9226-9231Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0903679106
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- National Institutes of Health [HL48675]
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The lengths of von Willebrand factor (VWF) concatamers correlate with hemostatic potency. After secretion in plasma, length is regulated by hydrodynamic shear force-dependent unfolding of the A2 domain, which is then cleaved by a specific protease. The 1.9-angstrom crystal structure of the A2 domain demonstrates evolutionary adaptations to this shear sensor function. Unique among VWF A (VWA) domains, A2 contains a loop in place of the alpha 4 helix, and a cis-proline. The central beta 4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the beta 4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal alpha 6-helix. The alpha 6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket. These features may narrow the force range over which unfolding occurs and may also slow refolding. Von Willebrand disease mutations, which presumably lower the force at which A2 unfolds, are illuminated by the structure.
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