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PDBsum entry 4c2b
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Blood clotting
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PDB id
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4c2b
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References listed in PDB file
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Key reference
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Title
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Structural basis of regulation of von willebrand factor binding to glycoprotein ib.
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Authors
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M.A.Blenner,
X.Dong,
T.A.Springer.
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Ref.
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J Biol Chem, 2014,
289,
5565-5579.
[DOI no: ]
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PubMed id
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Abstract
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Activation by elongational flow of von Willebrand factor (VWF) is critical for
primary hemostasis. Mutations causing type 2B von Willebrand disease (VWD),
platelet-type VWD (PT-VWD), and tensile force each increase affinity of the VWF
A1 domain and platelet glycoprotein Ibα (GPIbα) for one another; however, the
structural basis for these observations remains elusive. Directed evolution was
used to discover a further gain-of-function mutation in A1 that shifts the long
range disulfide bond by one residue. We solved multiple crystal structures of
this mutant A1 and A1 containing two VWD mutations complexed with GPIbα
containing two PT-VWD mutations. We observed a gained interaction between A1 and
the central leucine-rich repeats (LRRs) of GPIbα, previously shown to be
important at high shear stress, and verified its importance mutationally. These
findings suggest that structural changes, including central GPIbα LRR-A1
contact, contribute to VWF affinity regulation. Among the mutant complexes,
variation in contacts and poor complementarity between the GPIbα β-finger and
the region of A1 harboring VWD mutations lead us to hypothesize that the
structures are on a pathway to, but have not yet reached, a force-induced super
high affinity state.
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