This Reactome event shows the association of the inhibitory SERPINA10:PROZ complex with FXa:FVa to prevent excessive coagulation.
Protein Z (PROZ), a vitamin K-dependent plasma protein, functions as a cofactor for protein Z-dependent protease inhibitor (ZPI, encoded by the SERPINA10 gene), enhancing ZPI-mediated inhibition of activated factor Xa (FXa) on phospholipid membranes (Han X et al., 2000; Rezaie AR et al., 2008; Huang X et al., 2010, 2019; Dayer MR, 2012). In plasma, PROZ circulates tightly bound to SERPINA10 (Tabatabai A et al., 2001). The SERPINA10:PROZ complex associates with the cell surface in a calcium-dependent manner through the interaction of the N-terminal γ-carboxyglutamic acid (Gla) domain of PROZ with phospholipid membranes (Han X et al., 2000; Huang X et al., 2008, 2010; Wei Z et al., 2009). The Gla domain of PROZ may also interact with the Gla domain of the FXa light chain (Rezaie AR et al., 2008). The C-terminal pseudo-catalytic domain of PROZ interacts with SERPINA10 (ZPI), facilitating association between SERPINA10 and FXa on the cell surface (Rezaie AR et al., 2008; Huang X et al., 2010; 2012; Qureshi SH et al., 2014). The reactive center loop (RCL) of SERPINA10 binds to the active site of FXa, forming a serpin-protease complex in which FXa is trapped as an acyl-enzyme intermediate (Rezaie AR et al., 2005; Chandrasekaran V. et al., 2009; Huang X et al., 2008, 2010 ). However, this trapping does not completely abrogate the catalytic activity of FXa, allowing FXa to cleave SERPINA10 at P1 (Y408) site (Han X et al., 2000; Huang X et al., 2008; 2010). PROZ significantly accelerates FXa inhibition by SERPINA10, forming a ternary complex (Huang X et al., 2010; Dayer MR 2012), from which PROZ may dissociate following FXa binding (Huang X et al., 2008, 2015). SERPINA10 effectively inhibits both free FXa and FVa-bound FXa within the prothrombinase complex, although inhibition of the latter occurs at a slower rate (Han X et al., 2000; Huang X et al., 2010, 2019).
