Factor XIIa directly converts prekallikrein to kallikrein, which circulates as a 1:1 molar complex with high molecular weight kininogen (HK). Cleavage of HK by kallikrein generates a pro-inflammatory peptide bradykinin. Bradykinin formed in the contact system acts through the G-protein–coupled bradykinin B2 receptor on the surface of endothelial cells and causes increased vascular permeability and vasodilation resulting in edema formation (Zuraw BL & Christiansen SC 2016). Under physiological conditions activated factor XIIa binds to plasma protease C1-esterase inhibitor (C1-INH or SERPING1) forming a stable and enzymatically inactive complex (Bock et al. 1986). SERPING1 (C1-INH) also binds to the active site of plasma kallikrein blocking the ability of plasma kallikrein to cleave HK and to activate factor XII (Schreiber AD et al. 1973). Defective SERPING1 causes dysregulation of the plasma kallikrein-kinin-system with overproduction of bradykinin due to uninhibited effects of activated factor XIIa and plasma kallikrein. SERPING1 deficiency is linked to the pathogenesis of hereditary angioedema (HAE), an autosomal dominant disorder that manifests as recurrent episodes of swelling involving the face, tongue, extremities, gastrointestinal tract, genitalia, and upper airways (Loules G et al. 2018; De Maat S et al. 2018). HAE has been divided into 3 types, 2 of which are attributable to mutant SERPING1 gene. In type I (± 85% of HAE patients with SERPING1 deficiency), mutations are located on any exon in the SERPING1 gene leading to low antigenic and functional levels of SERPING1 due to defective expression of one allele. The type I HAE-linked variants of SERPING1 are thought to negatively affect synthesis, intracellular transport or secretion of the normal SERPING1 (Kramer J et al. 1993; Verpy E et al. 1993; Ernst SC et al. 1996; Haslund D et al. 2019). In a subset of patients with type I HAE, defective SERPING1 variants interact with wildtype (wt) SERPING1 in a dominant-negative manner and form intracellular SERPING1 aggregates leading to a reduction in the plasma levels of wt SERPING1 (Haslund D et al. 2019). Importantly, in patient-derived fibroblasts, the administration of wt SERPING1 gene was able to restore the levels of secreted SERPING1 (C1-INH) protein, suggesting that dominant-negative disease mechanisms can be overcome by gene supplementation (Haslund D et al. 2019). Further, administration of plasma-derived SERPING1 increased plasma levels of physiologically relevant functional SERPING1 in patients with HAE (Martinez-Saguer I et al. 2014; Riedl MA et al. 2016; Zuraw BL et al. 2015). In type II HAE (±15% of HAE patients), characterized by normal or elevated levels of dysfunctional SERPING1 (C1-INH) protein, mutations are mostly located in exon 8 of the SERPING1 gene (Verpy E et al. 1995). Exon 8 encodes the reactive center loop (RCL) and the hinge region of SERPING1 which have an important role in protein function (Verpy E et al. 1995). This classification of HAE types has however been challenged by observations of intermediate HAE types, that can arise when a small amount of dysfunctional SERPING1 is present in the blood stream (Eldering E et al. 1995; Verpy E et al. 1995; Madsen DE et al. 2014).
SERPING1 belongs to the serine protease inhibitor (serpin) superfamily of structurally similar but functionally diverse proteins that use a conformational change to inhibit target enzymes (Silverman GA et al. 2001; Gettins PG 2002; Law RH et al. 2006). Serpins are globular proteins with a conserved structure of 7- 9 α-helices and 3 β-pleated sheets and a protruding reactive center loop (RCL) (Silverman GA et al. 2001; Gettins PG 2002; Law RH et al. 2006; Sanrattana W et al. 2019). In native serpins, the RCL, located outside the tertiary core of the serpin, forms a flexible stretch of approximately 20 amino acids, which provides structural flexibility in a solvent-exposed environment. They act on their target proteases by means of a suicide-substrate mechanism involving the cleavage of the RCL and its insertion into β-sheet A (Gettins PG 2002; Pan S et al. 2011; Khan MS et al. 2011). As a result, conformational changes take place in the serpins that ultimately trap and inactivate the targeted protease (Gettins PG 2002; Pan S et al. 2011; Khan MS et al. 2011; Sanrattana W et al. 2019). Serpins are conformationally labile and many of the disease-linked mutations of serpins result in misfolding or in pathogenic, inactive polymers (Law RH et al. 2006).
The Reactome event describes failed interaction between SERPING1 variants and factor XIIa as the result of point mutations in or near RCL of SERPING1, for example at residues Arg466 or Ala458. The set of SERPING1 variants also includes a SERPING1 variant with deletion of Lys273 which results in acquisition of an N-glycosylation site leading to dysfunctional protein. The variants annotated in this event were identified in patients with type II HAE.
