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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-03-0789.
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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1699-1706
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The role of the D1 domain of the von Willebrand factor
propeptide in multimerization of VWF
Jonathan B. Rosenberg,
Sandra L. Haberichter,
Mary A. Jozwiak,
Elizabeth A. Vokac,
Philip A. Kroner,
Scot A. Fahs,
Yohko Kawai, and
Robert R. Montgomery
From the Blood Research Institute, The Blood Center of
Southeastern Wisconsin, and the Department of Pediatrics, The Medical
College of Wisconsin, Milwaukee.
While studying patient plasma containing an unusual pattern of von
Willebrand factor (VWF) multimers, we discovered a previously unreported phenomenon: heavy predominance of dimeric VWF. Genomic analysis revealed a new congenital mutation (Tyr87Ser) that
altered the final stages of VWF biosynthesis. This mutation in the
propeptide (VWFpp) resulted in synthesis of dimeric VWF with an almost
complete loss of N-terminal multimerization. The multimer pattern in
patient plasma appears to result from separate alleles' synthesizing
wild-type or mutant (dimeric) VWF, with homodimers composing the
predominant protomeric species. We have expressed VWF protein
containing the Tyr87Ser mutation and analyzed the intracellular
processing and resulting VWF biological functions. The expressed
dimeric VWF displayed a loss of several specific functions: collagen
binding, factor VIII binding, and ristocetin-induced platelet binding. However, granular storage of dimeric VWF was normal, demonstrating that
the lack of multimerization does not preclude granular storage. Although the tertiary structure of the VWFpp remains unknown, the
mutant amino acid is located in a region that is highly conserved across several species and may play a major role in the multimerization of VWF. Our data suggest that one function of the highly cysteine-rich VWFpp is to align the adjacent subunits of VWF into the correct configuration, serving as an intramolecular chaperone. The integrity of
the VWFpp is essential to maintain the proper spacing and alignment of
the multiple cysteines in the VWFpp and N-terminus of the mature VWF.
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