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PDBsum entry 1auq
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the von willebrand factor a1 domain and implications for the binding of platelet glycoprotein ib.
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Authors
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J.Emsley,
M.Cruz,
R.Handin,
R.Liddington.
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Ref.
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J Biol Chem, 1998,
273,
10396-10401.
[DOI no: ]
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PubMed id
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Abstract
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von Willebrand Factor (vWF) is a multimeric protein that mediates platelet
adhesion to exposed subendothelium at sites of vascular injury under conditions
of high flow/shear. The A1 domain of vWF (vWF-A1) forms the principal binding
site for platelet glycoprotein Ib (GpIb), an interaction that is tightly
regulated. We report here the crystal structure of the vWF-A1 domain at 2.3-A
resolution. As expected, the overall fold is similar to that of the vWF-A3 and
integrin I domains. However, the structure also contains N- and C-terminal arms
that wrap across the lower surface of the domain. Unlike the integrin I domains,
vWF-A1 does not contain a metal ion-dependent adhesion site motif. Analysis of
the available mutagenesis data suggests that the activator botrocetin binds to
the right-hand face of the domain containing helices alpha5 and alpha6. Possible
binding sites for GpIb are the front and upper surfaces of the domain. Natural
mutations that lead to constitutive GpIb binding (von Willebrand type IIb
disease) cluster in a different site, at the interface between the lower surface
and the terminal arms, suggesting that they disrupt a regulatory region rather
than forming part of the primary GpIb binding site. A possible pathway for
propagating structural changes from the regulatory region to the ligand-binding
surface is discussed.
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Figure 2.
Fig. 2. Stereo C  plot
comparing vWF-A1 (solid lines) with vWF-A3 (dashed lines). The
two molecules have been superimposed using MULTIFIT (25). The N
and C termini of vWF-A1 are labeled. Every 10th residue
(starting at 506) is shown as a small circle, with occasional
numbering. The N- and C-proximal cysteines forming the disulfide
bridge are shown as large circles.
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Figure 3.
Fig. 3. Main chain schematic of the vWF-A1 domain, with
 -strands
(arrows) and helices (coils) (drawn with MOLSCRIPT, RASTER3D,
and RENDER (32-34)). The two cysteines involved the disulfide
bridge are shown as yellow spheres. Sites of von Willebrand
disease type IIb mutations (both natural and induced) are shown
as red spheres. Mutants with reduced botrocetin binding are in
green. Mutations with selective loss-of-function (reduced
ristocetin-induced binding but normal botrocetin-induced
binding) are in cyan (23) or black (26), and a mutant with
reduced GpIb binding but normal botrocetin binding is in blue
(23). The mutation of KKKK642-645 in the 5- E loop also
reduces binding to heparin (26). For multiple site mutants,
spheres are placed near the midpoint of the mutation.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(1998,
273,
10396-10401)
copyright 1998.
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