VWF multimer binds to collagen type I

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). <p>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).

冯·维勒布兰德因子（VWF）是血小板-内皮细胞以及血小板-血小板相互作用中的关键组分。VWF以多聚体形式在血浆中循环，能够感知血液流中的流体剪切力（Reininger AJ 2008；Mojzisch A & Brehm MA 2021）。在血管损伤的情况下，循环中的VWF会与暴露于流动血液中的亚内皮胶原结合（Bergmeier W & Hynes RO 2012；Colace TV & Diamond SL 2013）。结构和生化分析揭示了I型和III型胶原与VWF的A3结构域结合（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）。IV型和VI型胶原与VWF的A1结构域相互作用（Hoylaerts MF et al.，1997；Mazzucato M et al.，1999；Flood VH et al.，2015）。冯·维勒布兰德病（VWD）2M型患者中VWF与胶原结合的缺陷（Flood VH et al.，2012；Favaloro EJ 2017；2020）是由VWF胶原结合域内的错义突变引起的（Morales LD et al.，2006；Posch S et al.，2018）。值得注意的是，VWF的A1结构域，对于与IV型和VI型胶原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结合缺陷（Bonnefoy A et al.，2006；Posch S et al.，2018）。与胶原结合后，VWF锚定于受损表面。剪切力随后诱导机械敏感的VWF发生构象变化，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A1结构域暴露，从而允许与糖蛋白Ib α（GPIbα，由GP1BA编码）结合，GPIbα是血小板表面GPIb-IX-V复合物的一个亚单位（Dumas JJ et al.，2004；Ju L et al.，2013）。因此，VWF通过与暴露的胶原和血小板相互作用，启动血小板对血管损伤部位的粘附。在正常生理条件下，VWF以折叠的、非活性形式循环，由于自身抑制性调节，不与血小板相互作用（Aponte-Santamaria C et al.，2015；Butera D et al.，2018；Arce NA et al.，2021；Zhao YC et al.，2022）。本Reactome事件展示了VWF多聚体与人体中最丰富的胶原之一——纤维素状I型胶原之间的相互作用（Shekhonin BV et al.，1987；Naomi R et al.，2021）。