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Plasma prekallikrein (KLKB1(20?638)), within the prekallikrein:kininogen:cell surface receptor:FXII complex, is cleaved by activated factor XII (FXIIa) (Revak SD et al. 1978; Shariat-Madar Z et al. 2002; reviewed by Renné T et al., 2012; Pathak M et al., 2018). The cell surface receptors involved in this process include complement C1q-binding protein (known as globular C1q receptor or gC1qR, encoded by the C1QBP gene), cytokeratin 1 (CK1, encoded by the KRT1 gene), and the urokinase plasminogen activator receptor (uPAR, encoded by the PLAUR gene). Both gC1qR (C1QBP) and uPAR (PLAUR) interact with CK1 (KRT1), forming heterodimers gC1qR:CK1 and uPAR:CK1, respectively. Additionally, gC1qR (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). In plasma, prekallikrein (KLKB1(20?638)) specifically associates with high-molecular-weight kininogen (HK, encoded by the KNG1 gene), which binds to cell surface receptor complexes, namely, gC1qR homotrimer, gC1qR:CK1, or uPAR:CK1. Although these receptors are expressed on various cell types, including activated platelets (Peerschke EIB et al., 2003; Khan MM et al., 2006; reviewed by Schmaier AH, 2016), activation of prekallikrein is thought to occur predominantly on endothelial cell surfaces (Lin Y et al., 1997; Motta G et al., 1998; Joseph K et al., 2001; Mahdi F et al., 2002, 2003; Pixley RA et al., 2011). On the cell surface, prekallikrein (KLKB1(20?638)) is converted to kallikrein, a heterodimer consisting of a light chain (KLKB1(391?638)) and a heavy chain (KLKB1(20?390)). Kallikrein may remain bound to the kininogen:cell surface receptor:FXII complex (Motta G et al., 1998; Zhao Y et al., 2001), where it subsequently cleaves kininogen, releasing bradykinin (Cochrane CG et al., 1973; Zhao Y et al., 2001). Bradykinin primarily binds to the kinin B2 receptor (B2R) to trigger inflammation. Furthermore, kallikrein amplifies the system by cleaving FXII into its active form, FXIIa, creating a positive feedback loop (reviewed by Renné T et al., 2012). Additionally, plasma prekallikrein is cleaved to its active form by prolylcarboxypeptidase, independent of FXIIa (Motta G et al., 1998; Shariat-Madar Z et al., 2002; Merkulova AA et al., 2023).
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