Functional Roles of the von Willebrand Factor Propeptide

Abstract

The primary polypeptide sequence of von Willebrand factor (VWF) includes an N-terminal 741-amino acid VWF propeptide (VWFpp). In cells expressing VWF, the VWFpp performs two critical functions. In the Golgi, VWFpp mediates the intermolecular disulfide linkages that generate high-molecular-weight VWF multimers. Subsequently, the VWFpp, which is proteolytically cleaved from mature VWF by furin, functions to generate the endothelial storage organelles (Weibel-Palade bodies) in which VWF and a distinct collection of proteins are stored, and from where they undergo regulated secretion from the endothelium. The VWFpp is secreted from endothelial cells as dimers and circulates in plasma with at least some of the dimers associating with a noncovalent manner with the D′D3 domain of mature VWF. The VWFpp has a half-life of 2 to 3 hours in plasma, but to date no extracellular function has been determined for the molecule. Nevertheless, its large size and several biologically interesting structural features (two sets of vicinal cysteines and an RGD sequence) suggest that there may be roles that the VWFpp plays in hemostasis or associated physiological processes such as angiogenesis or wound repair.

von Willebrand factor propeptide missense variants affect anterograde transport to Golgi resulting in ER retention

“…(affecting N-glycan attachment site) and p.Gly334Glu on the probabale functions of VWFpp in circulation remains to be understood (Rawley & Lillicrap, 2021).…”

“…On the basis of our observations, we suggest these two variants should be considered benign variants rather than pathologic mutations. Nonetheless, due to the current suggested potential roles of VWFpp in hemostasis or associated physiological processes, such as angiogenesis and wound repair, the impact of the variants p.Asn211Asp (affecting N‐glycan attachment site) and p.Gly334Glu on the probabale functions of VWFpp in circulation remains to be understood (Rawley & Lillicrap, 2021).…”

von Willebrand factor propeptide variants lead to impaired storage and ER retention in patient‐derived endothelial colony‐forming cells

“…Additionally, and/or alternatively, it has been suggested that there may also be an extracellular role for the VWF propeptide in hemostasis. 36 For individuals with variants in the VWF propeptide perhaps this function is also impaired or abolished and contributes to the increased bleeding.…”

“…The findings in the present study may point to some reasons for this increased bleeding potential including the absence of WPBs leading to the improper storage/release of other cargo proteins. Additionally, and/or alternatively, it has been suggested that there may also be an extracellular role for the VWF propeptide in hemostasis 36 . For individuals with variants in the VWF propeptide perhaps this function is also impaired or abolished and contributes to the increased bleeding.…”

Quantitative super-resolution imaging of platelet degranulation reveals differential release of VWF and VWF propeptide from alpha-granules

“…Possibly, focused release of VWFpp from degranulating platelets during the initial thrombus formation and incorporation in the adhesive surface via laminin and collagen provides a mechanism to influence the adhesive properties of the exposed extracellular matrix and direct hemostatic and immune responses following vascular injury. Recent reports have emerged that VWFpp can support platelet adhesion to collagen surfaces and enhance thrombus mass in a glycan-dependent manner [50] and that in a murine model of deep vein thrombosis VWFpp incorporates in venous thrombi near regions of active thrombus formation [51].…”