Von Willebrand factor (VWF) is an essential component in platelet-endothelium and platelet-platelet interactions. VWF circulates in plasma as a multimeric molecule that senses hydrodynamic shear forces in the bloodstream (Reininger AJ 2008; Mojzisch A & Brehm MA 2021). Upon vascular injury, circulating VWF binds to subendothelial collagen which becomes exposed to the flowing blood (Bergmeier W & Hynes RO 2012; Colace TV & Diamond SL 2013). Structural and biochemical analysis have revealed that collagen types I and III bind to the A3 domain of VWF (Lankhof H et al., 1996; Huizinga EG et al., 1997; Romijn RA et al., 2003; Nishida N et al., 2003; Brondijk THC et al., 2012). Collagen types IV and VI interact with the A1 domain of VWF (Hoylaerts MF et al., 1997; Mazzucato M et al., 1999; Flood VH et al., 2015). Impaired binding of VWF to collagen in patients with von Willebrand disease (VWD) type 2M (Flood VH et al., 2012; Favaloro EJ 2017; 2020) is caused by missense mutations within the collagen-binding domains of VWF (Morales LD et al., 2006; Posch S et al., 2018). It is worth noting that the A1 domain of VWF, which is essential for the interaction with collagen type IV and VI, can compensate for a defective collagen binding caused by mutations in the A3 domain (Bonnefoy A et al., 2006; Posch S et al., 2018). 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). Thus, VWF interacts both with exposed collagen and platelets to initiate platelet adhesion to vascular injury sites. Under normal physiological conditions, VWF circulates in a folded, inactive form, which does not interact with platelets due to autoinhibitory regulation (Aponte-Santamaria C et al., 2015; Butera D et al., 2018; Arce NA et al., 2021; Zhao YC et al., 2022).
This Reactome event shows interaction between VWF multimer and fibrillar collagen type I, which is one of the most abundant collagens in the human body (Shekhonin BV et al., 1987; Naomi R et al., 2021).
