Characterization of Zebrafish von Willebrand Factor Reveals Conservation of Domain Structure, Multimerization, and Intracellular Storage

摘要

Vertebrates possess a complex closed circulatory system that requires balanced coordination of various factors that serve to maintain blood flow as well as prevent exsanguination when the system is breached. This is known as hemostasis and consists of a complex array of cellular elements, as well as a network of proteins known as the coagulation cascade. The latter have been highly conserved at the genomic level throughout vertebrate evolution, including mammals, birds, reptiles, and fish. One of the central components of coagulation is von Willebrand factor (VWF), deficiencies of which are the basis for the bleeding disorder von Willebrand disease (VWD). The mammalian VWF gene consists of 52 exons, and the largest, exon 28, contains several functional domains that are frequently mutated in VWD. VWF is a 260 kDa (kilodalton) secreted glycoprotein that assembles into mul-timers of over 10,000 kDa. At sites of injury, high molecular weight VWF multimers bind to receptors in the vascular subendothelium and tether platelets to form the primary hemostatic plug. Much of our knowledge of VWF function is derived from characterization of mutations in humans and various mammalian model organisms, including mouse, dog, horse, cat, pig, and rabbit. However, relatively little information is available in other vertebrate models, such as the teleost Danio rerio (zebrafish).