| text | In circulation, von Willebrand factor (VWF) multimers detect vessel injuries and mediate platelet adhesion to vascular injury sites (Reininger AJ, 2008; Mojzisch A & Brehm MA, 2021). VWF also serves as a carrier protein for factor VIII (FVIII), stabilizing FVIII, which otherwise exhibits a very short half-life in the bloodstream (Kaufman RJ et al., 1997). The activity of VWF depends on its multimerization state, with larger multimers displaying higher thrombogenic potential and enhanced platelet tethering capacity at vascular injury sites. Under normal physiological conditions, ultra-large VWF multimers are cleaved into smaller units by the shear-dependent enzyme ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13) (Shim K et al., 2008; Zhang X et al., 2009). ADAMTS13 regulates VWF procoagulant activity by cleaving the peptide bond between Tyr1605 and Met1606 within the VWF A2 domain (Furlan M et al., 1996; Tsai HM, 1996; Crawley JTB et al., 2011). ADAMTS13 is primarily produced by hepatic stellate cells in the liver and secreted into circulation as an inactive (closed) enzyme (Zhou W et al., 2005). The closed conformation of ADAMTS13 is maintained through interactions between its C-terminal CUB1-2 domains and spacer domain (South K et al., 2014; Kim HJ et al., 2021; reviewed in Ercig B et al., 2021). Structural studies reveal that ADAMTS13 becomes proteolytically active upon binding to VWF (Crawley JTB et al., 2011; South K et al., 2014; Petri A et al., 2019; Geist N et al., 2022). VWF cleavage by ADAMTS13 occurs on endothelial cell surfaces during VWF secretion or at sites of vascular damage, where VWF binds exposed collagen and forms VWF‑platelet strings (Dong JF et al., 2003; Shim K et al., 2008; Turner N et al., 2008). Additionally, VWF cleavage has been detected in circulating blood (Majerus EM et al., 2005). Factor VIII (FVIII) enhances VWF cleavage by ADAMTS13 in vitro under shear stress, likely by altering VWF conformation to make the cleavage site more accessible (Skipwith CG et al., 2010; Cao W et al., 2008, 2020). VWF variants with reduced FVIII-binding capacity, as observed in type 2N von Willebrand disease (VWD), exhibit impaired shear-dependent VWF proteolysis by ADAMTS13 in the presence of FVIII (Skipwith CG et al., 2013). In vivo studies further support the regulatory role of FVIII in VWF cleavage by ADAMTS13 (Kiouptsi K et al., 2017; Cao W et al., 2012, 2023). This Reactome event shows ADAMTS13-catalyzed cleavage of FVIII-bound VWF at Tyr1605–Met1606. ADAMTS13 binding to VWF is controlled by the conformational changes in the mechanosensitive VWF multimer, which undergoes shear stress-induced transition from a folded, inactive conformation to an unfolded, elongated VWF multimers. In the inactive state, VWF is stabilized by autoinhibitory interdomain interactions that mask binding sites for platelets and ADAMTS13 within the A1 and A2 domain of VWF, respectively (Aponte-Santamaría C et al., 2015; Arce NA et al., 2021; Bonazza K et al., 2022; Zhao YC et al., 2022). The A2 domain's stability is further supported by a Ca²⁺ ion-binding site and a vicinal disulfide bond (Cys1669–Cys1670) (Xu AJ & Springer TA, 2012; Lynch CJ et al., 2014). Shear-induced destabilization of the A2 domain of VWF results in exposing Tyr1605-Met1606 to ADAMTS13 (Zhang X et al., 2009; Baldauf C et al., 2009; Crawley JTB et al., 2011; Petri A et al., 2019). The ADAMTS13:VWF interaction involves multiple contact sites (Gao W et al., 2008; de Groot R et al., 2015; South K et al., 2017; Kretz CA et al., 2018; Petri A et al., 2019; Geist N et al., 2022; reviewed by Crawley JTB et al., 2011; DeYoung V et al., 2022). Surface plasmon resonance and equilibrium binding assays suggest that interactions between ADAMTS13's CUB1-2 domains and the VWF D4-CK domain release the spacer domain (South K et al., 2017). Kinetic analyses indicate that unfolded VWF A2 domains are recognized by exosites within ADAMTS13's cysteine-rich and spacer domains, facilitating proximity between VWF and ADAMTS13 (Petri A et al., 2019). This binding allosterically activates the metalloprotease domain of ADAMTS13, enabling VWF cleavage (Petri A et al., 2019; Geist N et al., 2022).
|
|---|
