The effect of mutated cysteine residues in von Willebrand factor

Abstract

Von Willebrand factor (VWF) plays an important role in both primary and secondary hemostasis as a molecular glue between platelets and subendothelial structures, and as a carrier of FVIII. Mutations in VWF may cause von Willebrand disease (VWD), which is the most common bleeding disorder. It is characterized by symptoms ranging from very mild to severe bleeding. Mutations may influence the level of VWF (quantitative defect; type 1 or type 3) or may affect the function of VWF. Especially important for the generation of functional VWF is the formation of disulfide linked bonds. Firstly, intrachain linking is essential for the monomer structure. Secondly, interchain linking is necessary for both dimerization and multimerization of VWF. All 169 cysteine residues in the mature VWF subunit (8.2%) participate in these intra- or interchain disulfide bonds. The interaction between proVWF dimers ultimately yields high-molecular weight VWF that is active in primary hemostasis in the bloodstream.The main aims of the studies reported in this thesis were to examine how loss of cysteines located in different domains of VWF results in quantitative and qualitative VWF defects; how these mutations interfere with dimerization and multimerization; and how they influence intracellular routing, secretion and clearance of VWF.