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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-07-2281.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1384-1391
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Critical independent regions in the VWF propeptide and mature
VWF that enable normal VWF storage
Sandra L. Haberichter,
Paula Jacobi, and
Robert R. Montgomery
From the Department of Pediatrics, Medical College of
Wisconsin, Milwaukee, WI; the Blood Research Institute, The Blood
Center of Southeastern Wisconsin, Milwaukee, WI; and Children's
Hospital of Wisconsin, Milwaukee, WI.
Von Willebrand factor (VWF) is synthesized in endothelial cells,
where it is stored in Weibel-Palade bodies. Administration of
1-desamino-8-D-arginine-vasopressin (DDAVP) to patients with type 1 von
Willebrand disease and to healthy individuals causes a rapid increase
in plasma VWF levels. This increase is the result of stimulated release
of VWF from Weibel-Palade bodies in certain beds of endothelial cells.
The VWF propeptide (VWFpp) targets VWF to storage granules through a
noncovalent association. The nature of the VWFpp/VWF interaction was
investigated by using cross-species differences in VWF storage. While
canine VWFpp traffics to storage granules and facilitates the
multimerization of human VWF, it does not direct human VWF to storage
granules. Since storage takes place after furin cleavage, this defect
appears to be due to the defective interaction of canine VWFpp and
human VWF. To determine the regions within VWFpp and VWF important for
this VWFpp/VWF association and costorage, a series of human-canine chimeric VWFpp and propeptide-deleted VWF ( pro) constructs were produced and expressed in AtT-20 cells. The intracellular localization of coexpressed proteins was examined by confocal microscopy. Two amino
acids, 416 in VWFpp and 869 in the mature VWF molecule, were identified
as being critical for the association and granular storage of VWF.
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