The prekallikrein (PK):kininogen (HK) complex, KLKB1(20–638):KNG1(19–644), binds to cell surface receptors in a Zn²⁺-dependent manner (Motta G et al., 1998). Prekallikrein (PK, depicted here as KLKB1(20–638)) can also bind directly to endothelial cell membranes in the absence of kininogen (HK, depicted here as KNG1(19–644)) (Motta G. et al., 1998). Through HK, the PK:HK complex binds cell surface receptors including complement C1q-binding protein (C1QBP, also known as globular C1q receptor or gC1qR), cytokeratin 1 (CK1, encoded by KRT1), and the urokinase plasminogen activator receptor (uPAR, encoded by PLAUR). Both gC1qR (C1QBP) and uPAR (PLAUR) interact with CK1 (KRT1), forming heterodimers C1QBP:CK1 and uPAR:CK1, respectively (Pixley RA et al, 2011). Additionally, C1QBP may function as a homotrimer (Ghebrehiwet B et al., 1994; Joseph K et al., 1999, 2001, 2004; Mahdi F et al., 2002, 2003; Kaira BG et al., 2020; reviewed by Pathak M et al., 2018). C1QBP (gC1qR) also forms a trimolecular complex with HK and FXII, binding at different regions on the protein (Kaira BG et al., 2020).
Surface binding of the prekallikrein:kininogen complex is also mediated through the association of kininogen (KNG1(19–644)) with negatively charged surfaces, such as glycosaminoglycans (GAGs) (DeLa Cadena RA & Colman RW, 1992; Herwald H et al., 2001) or cell surface proteins (Mahdi F et al., 2002; Pixley RA et al., 2011; Kaira BG et al., 2020). Zn²⁺-dependent binding of kininogen to surfaces positions prekallikrein (KLKB1(20–638)) in proximity to these surfaces, facilitating its activation (Ghebrehiwet B et al., 1994; Joseph K et al., 1999, 2004; Mahdi F et al., 2002, 2003). Specifically, domain 6 of kininogen binds prekallikrein (Thompson RE et al., 1979; Tait JF & Fujikawa K, 1987), while domain 5 binds Zn²⁺ and surfaces (DeLa Cadena & Colman, 1992; Herwald et al., 2001; Pixley et al., 2011).
In the context of the contact activation system, the binding of kininogen to either the C1QBP (gC1qR) homotrimer, C1QBP:CK1, or uPAR:CK1 complexes facilitate the assembly of kininogen, prekallikrein, and FXII into higher-order ternary complexes. Within these complexes, FXII and prekallikrein reciprocally activate each other in a Zn²⁺-dependent manner (Joseph K et al., 1996, 1999, 2004; Mahdi F et al., 2002, 2003; Kaira BG et al., 2020). Among these receptors, C1QBP (gC1qR) exhibits the highest affinity for kininogen (Joseph K et al., 2004; Pixley RA et al., 2011).
Prekallikrein activation predominantly occurs on endothelial cell surfaces (Lin Y et al., 1997; Motta G et al., 1998; Joseph K et al., 2001; Mahdi F et al., 2003). However, other cell types, such as activated platelets, can also expose negatively charged surfaces or express cell surface receptors that contribute to kallikrein-kinin system (KKS) activation (reviewed by Schmaier AH, 2016). Neutrophils may also serve as sites for assembly and activation of FXII and the proteins of the plasma kallikrein/kinin system (Gustafson EJ et al., 1989, Stavrou EX et al., 2018).
