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).
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).
This Reactome event shows defective binding of VWF to collagen type I caused by mutations in the A3 domain of VWF.