VWF variant does not bind GPIb:IX:V

Upon vascular injury, subendothelial extracellular matrix components including collagen become exposed to the flowing blood (Bergmeier W & Hynes RO 2012). Circulating von Willebrand factor (VWF) binds to exposed vascular collagen (Colace TV & Diamond SL 2013). Upon binding to collagen, VWF becomes anchored to the damaged surface. Shear forces then induce conformational changes to mechanosensitive VWF causing the bound VWF to stretch and unfold (Li F et al., 2004; Schneider SW et al., 2007; Fu H et al., 2017). VWF unfolding leads to exposure of the A1 domain to allow binding to glycoprotein Ib α (GPIbα, encoded by GP1BA), a subunit of the platelet surface GPIb:IX:V complex (Dumas JJ et al. 2004; Ju L et al., 2013). This Reactome event describes von Willebrand disease (VWD)-associated missense mutations in the A1 domain of VWF, namely VWF S1358N, S1387I, S1394F and Q1402P, that compromise the clot formation. These VWF variants showed normal levels of expression, secretion, and multimerization but reduced binding to platelets (Larsen DM et al. 2013).

在血管损伤后，内皮细胞外基质成分，包括胶原蛋白，暴露于流动血液之中（Bergmeier W & Hynes RO 2012）。循环中的冯·维勒布兰特因子（VWF）与暴露的血管胶原蛋白（Colace TV & Diamond SL 2013）结合。VWF与胶原蛋白结合后，将锚定于损伤表面。随后，切应力引发对机械敏感的VWF的构象变化，导致结合的VWF拉伸和展开（Li F et al., 2004；Schneider SW et al., 2007；Fu H et al., 2017）。VWF的展开导致其A1结构域暴露，从而允许与糖蛋白Ibα（GPIbα，由GP1BA编码）结合，后者为血小板表面GPIb:IX:V复合物的一个亚基（Dumas JJ et al. 2004；Ju L et al., 2013）。此Reactome事件描述了与冯·维勒布兰特病（VWD）相关的VWF A1结构域中的错义突变，包括VWF S1358N、S1387I、S1394F和Q1402P，这些突变损害了凝血过程。这些VWF变异体表现出正常的表达、分泌和寡聚化水平，但与血小板的结合能力降低（Larsen DM et al. 2013）。