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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-03-0789.
Submitted March 13, 2002
Accepted April 17, 2002
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*
Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA
Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA; Department of Pediatrics, The Medical College of Wisconsin, Milwaukee, WI, USA
Department of Pediatrics, The Medical College of Wisconsin, Milwaukee, WI, USA
Department of Pediatrics, The Medical College of Wisconsin, Milwaukee, WI, USA; Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA
* Corresponding author; email: bob{at}bcsew.edu.
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 (Y87S) 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 comprising the predominant protomeric species. We have expressed VWF protein containing the Y87S 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 must 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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