VWF variant does not bind to collagen type I

Under normal physiological conditions, von Willebrand factor (VWF) circulates in plasma as a multimeric molecule in a folded, inactive form. VWF acts as a sensor of hydrodynamic shear forces in the bloodstream (Reininger AJ 2008; Mojzisch A & Brehm MA 2021). Upon vascular injury, subendothelial extracellular matrix components including collagen become exposed to the flowing blood (Bergmeier W & Hynes RO 2012). Circulating VWF binds to exposed vascular collagen (Colace TV & Diamond SL 2013). Structural and biochemical analyses have revealed that the binding site for collagen types I and III is located within the A3 domain of VWF (Lankhof H et al., 1996; Huizinga EG et al., 1997; Nishida N et al., 2003). Collagen types IV and VI interact with the A1 domain of VWF (Hoylaerts MF et al., 1997; Flood VH et al., 2015).<p>Loss-of-function mutations in the A1 and A3 domains of VWF are associated with von Willebrand disease (VWD) type 2M, which is characterized by defects in platelet adhesion and/or collagen binding with normal or subnormal VWF multimer distribution. Functional studies on VWD-associated missense mutations in the A3 domain of VWF showed a reduced binding of VWF S1783A, W1745C and H1786D variants to collagen type I and type III (Riddell AF et al., 2009; Flood VH et al., 2010; Shida Y etal., 2014). Similar results were reported for VWF L1733P (Shigekiyo T et al., 2020). Studies on the VWF S1731T variant demonstrated affected binding to collagen type I, but reported controversial results on binding to collagen type III (Ribba AS et al., 2001; Riddell AF et al., 2009; Flood VH et al., 2010; Shida Y et al., 2014; Maas D et al., 2022). Normal high molecular weight multimer formation and distribution was reported for all of the above-mentioned variants (Riddell AF et al., 2009; Flood VH et al., 2010; Shida Y et al., 2014). Further, kinetic studies on interactions of VWF variants (S1731T and H1786D) with collagen type III and VI using single-molecule force spectroscopy suggest that the A1 domain of VWF, which is essential for the interaction with collagen type IV and VI, can compensate a defective collagen binding caused by mutations in the A3 domain (Posch S et al., 2018).<p>This Reactome event shows defective binding of VWF to collagen type I caused by mutations in the A3 domain of VWF.

在正常的生理状态下，冯·维勒布兰德因子（VWF）以折叠的、非活性形式作为多聚体分子在血浆中循环。VWF作为血液流中流体剪切力的传感器（Reininger AJ 2008；Mojzisch A & Brehm MA 2021）。在血管损伤的情况下，内皮下细胞外基质成分，包括胶原蛋白，暴露于流动的血液中（Bergmeier W & Hynes RO 2012）。循环中的VWF与暴露的血管胶原蛋白（Colace TV & Diamond SL 2013）结合。结构和生化分析揭示了胶原蛋白I型和III型的结合位点位于VWF的A3结构域内（Lankhof H et al.，1996；Huizinga EG et al.，1997；Nishida N et al.，2003）。胶原蛋白IV型和VI型与VWF的A1结构域相互作用（Hoylaerts MF et al.，1997；Flood VH et al.，2015）。VWF A1和A3结构域的失活突变与冯·维勒布兰德病（VWD）2M型相关，该病以血小板粘附缺陷和/或与胶原蛋白结合缺陷为特征，而VWF多聚体的分布正常或低于正常水平。对VWD相关A3结构域的错义突变的功能研究表明，VWF S1783A、W1745C和H1786D变异体与胶原蛋白I型和III型的结合减少（Riddell AF et al.，2009；Flood VH et al.，2010；Shida Y et al.，2014）。对于VWF L1733P变异体也有类似的报道（Shigekiyo T et al.，2020）。关于VWF S1731T变异体的研究显示其对胶原蛋白I型的结合受影响，但在胶原蛋白III型的结合上却出现了相互矛盾的结论（Ribba AS et al.，2001；Riddell AF et al.，2009；Flood VH et al.，2010；Shida Y et al.，2014；Maas D et al.，2022）。所有上述变异体均报道了正常的高分子量多聚体的形成和分布。此外，使用单分子力谱对VWF变异体（S1731T和H1786D）与胶原蛋白III型和VI型的相互作用进行的动力学研究表明，VWF的A1结构域，对于与胶原蛋白IV型和VI型的相互作用至关重要，可以补偿由A3结构域突变引起的胶原蛋白结合缺陷（Posch S et al.，2018）。本Reactome事件展示了VWF由于VWF A3结构域的突变而导致的与胶原蛋白I型结合缺陷。