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 \u03b1-helices and 3 \u03b2-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 \u03b2-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.", "cellular_location": "extracellular region", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "P00748-1" ], "evidence": [ { "id": "R-HSA-9651456", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9651456" } ] }, { "id": "R-HSA-9653249", "name": "Cleavage of factor XII variant by activated thrombin", "equation": "", "summary": "The plasma protein factor XII (FXII, F12 or Hageman factor) is a serine protease that is mainly produced in the liver and circulates in plasma (40\u202f\u03bcg/mL) as a single chain zymogen. Following contact with anionic surfaces such as extracellular RNA, endotoxin, neutrophil extracellular traps (NETs), polyphosphates released from activated platelets, collagen exposed on injured endothelium, heparin secreted from mast cells, and phosphatidylserine on apoptotic cells, FXII undergoes autoactivation to FXIIa (F12a) via proteolysis of the peptide bond R372-V373 in FXII zymogen (Renn\u00e9 T et al. 2012; M\u00fcller F et al. 2009; Oschatz C et al. 2011; Ivanov I et al. 2017; Mailer RKW et al. 2019). Active protease FXIIa is composed of a heavy (20-372) chain and a light (373-615) chain. The light chain harbors the enzymatic protease domain and is linked to the heavy chain by a single disulfide bridge. FXIIa then cleaves plasma prekallikrein to kallikrein, which in turn reciprocally activates additional molecules of FXII and amplifies FXIIa generation (Renn\u00e9 T et al. 2012). Kallikrein also cleaves high-molecular-weight kininogen (HK), releasing the vasoactive peptide bradykinin (BK) (Renn\u00e9 T et al. 2012). BK binds to kinin receptors (B2 and B1 receptors) and triggers inflammation (Leeb-Lundberg LM et al. 2005). The contact system is controlled mainly by C1 inhibitor (C1-Inh or SERPING1) that inhibits both FXIIa and kallikrein.
Hereditary angioedema (HAE) is a rare life-threatening inherited edema disorder that is characterized by recurrent episodes of acute swelling involving the skin or the oropharyngeal, laryngeal, or gastrointestinal mucosa (Zuraw BL & Christiansen SC 2016; de Maat S et al. 2018; Magerl M et al. 2017). Increased vascular permeability in HAE is due to excessive formation of the proinflammatory peptide hormone bradykinin (BK) (Joseph K et al. 2008). Elevated plasma levels of BK are consistently found during acute swelling attacks in HAE patients (Schapira M et al. 1983; Cugno M et al. 2003). Angioedema initiated by bradykinin is usually associated with SERPING1 (\u04211-Inh) deficiency (HAE type I and HAE type II) (Kaplan AP & Joseph K 2014, 2016; Levi M et al. 2018). More rarely, HAE occurs in individuals with normal SERPING1 activity, and has been linked to mutations in other proteins, including FXII, plasminogen, and angiopoietin (Magerl M et al. 2017; Zuraw BL 2018; Ivanov I et al. 2019). Using genome-wide linkage analyses, HAE type III was shown to be associated with single missense mutations (c.1032C>A or c.1032C>G) in the F12 gene (Dewald G & Bork K 2006; Cichon S et al. 2006). Both point mutations translate into amino acid substitution of threonine 328 by either a lysine or an arginine residue (T328K or T328R). FXII-linked HAE is an autosomal dominant inherited disorder, and a mixture of wild type and T328-mutated FXII circulates in plasma of patients with HAE type III (Cichon S et al. 2006). An FXII-neutralizing antibody attenuated pathological BK formation in the plasma of patients with HAE type III and blunted edema in a genetically altered, humanized mouse model of HAE type III (Bj\u00f6rkqvist J et al. 2015). Moreover, FXII T328K or T328R variants change protein O-linked glycosylation and introduce a new site that is sensitive to enzymatic cleavage by fibrinolytic and coagulation proteases such as plasmin, thrombin or FXIa (Bj\u00f6rkqvist J et al. 2015; de Maat S et al. 2016; Ivanov I et al. 2019). FXII T328K or T328R variants are cleaved after residue 328 by proteases, removing the protein\u2019s noncatalytic heavy chain (HC) region. Further, truncation of the pathological FXII T328K by plasmin was found to expose R372 for subsequent cleavage by plasma kallikrein in solution (de Maat S et al. 2016, 2019). The intrinsic capacity of the truncated form of FXII (329-615) variant to convert PK to kallikrein is greater than that of activated FXIIa leading to more kallikrein generated early during reciprocal activation (Ivanov I et al. 2019). Second, the truncated form of FXII (329-615) is a better kallikrein substrate than is FXII (Ivanov I et al. 2019). SERPING1 (C1-Inh), the major inhibitor of FXIIa, binds similarly to wild type (WT) and mutated FXIIa (Bj\u00f6rkqvist J et al. 2015). However, the accelerated kallikrein/FXII activation in HAE patients carrying FXII variants appears to overwhelm the regulatory function of SERPING1 at normal plasma levels leading to uncontrolled bradykinin formation in a surface-independent manner (de Maat S et al. 2016; Ivanov I et al. 2019).
The Reactome event describes a truncation of FXII variants after the residue 328 catalyzed by activated thrombin.", "cellular_location": "extracellular region, plasma membrane", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "P00734-1", "P00748-1" ], "evidence": [ { "id": "R-HSA-9653249", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9653249" } ] }, { "id": "R-HSA-9655046", "name": "Cleavage of FXII variant by KLKB1", "equation": "", "summary": "In healthy individuals, cleavage of a single peptide bond converts factor XII (FXII, F12, Hageman factor) to activated FXII (FXIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). FXII undergoes autoactivation to FXIIa either by endogenous activator (nucleic acids RNA/DNA, neutrophil extracellular traps (NETs), polyphosphate and heparin) or artificial surfaces. FXIIa then activates four different pathways: 1) The inflammation kallikrein-kinin pathway by converting plasma pre-kallikrein (PK) into active plasma kallikrein, which cleaves both FXII into FXIIa and high molecular weight kininogen (HK) to bradykinin (BK). The latter binds to kinin receptors (B2 and B1 receptors) and triggers inflammation. 2) The complement system by activation of the C1qrs complex subunits C1r and C1s leading formation of the membrane attack complex by the classical complement pathway. 3) The fibrinolytic system by activation of pro-urokinase into urokinase that in turn cleaves plasminogen into plasmin, an enzyme that degrades fibrin clots. 4) The intrinsic coagulation pathway by FXI activation into FXIa leading to thrombin activation and fibrin generation. The contact system is controlled mainly by C1 inhibitor (C1-Inh or SERPING1) that inhibits both FXIIa and kallikrein.
Patients with hereditary angioedema (HAE) experience episodes of soft tissue swelling as a consequence of unregulated kallikrein activity or increased prekallikrein activation. Angioedema initiated by bradykinin is usually associated with SERPING1 deficiency. More rarely, HAE occurs in individuals with normal SERPING1 activity, and has been linked to mutations in other proteins, including FXII, plasminogen, and angiopoietin (Magerl M et al. 2017; Zuraw BL 2018; Ivanov I et al. 2019). The substitution of threonine 328 by either a lysine or an arginine residue (T328K or T328R) in the FXII proline-rich region have been identified in several families with HAE and normal SEPING1. FXII T328K or T328R variants change protein glycosylation and introduce a new site that is sensitive to enzymatic cleavage by fibrinolytic and coagulation proteases such as plasmin, thrombin or FXIa (de Maat S et al. 2016; Ivanov I et al. 2019). FXII T328K or T328R variants are cleaved after residue 328 by proteases, removing the protein\u2019s noncatalytic heavy chain (HC) region. Truncation of the pathological FXII T309K by plasmin exposes R372 for subsequent cleavage by plasma kallikrein in solution (de Maat S et al. 2016, 2019). The intrinsic capacity of the truncated form of FXII (329-615) to convert PK to kallikrein is greater than that of activated FXII leading to more kallikrein generated early during reciprocal activation (Ivanov I et al. 2019). Second, the truncated form of FXII (329-615) is a better kallikrein substrate than is FXII (Ivanov I et al. 2019). Further, the accelerated PK/FXII activation in HAE patients carrying FXII variants appears to overwhelm the regulatory function of SERPING1 at normal plasma levels leading to uncontrolled bradykinin formation in a surface-independent manner (de Maat S et al. 2016; Ivanov I et al. 2019).", "cellular_location": "extracellular region", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "P00748-1", "P03952-1" ], "evidence": [ { "id": "R-HSA-9655046", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9655046" } ] } ], "reaction_participants": [ { "participant_id": "R-HSA-158214", "participant_name": "factor XII [plasma membrane]", "crossref": [ { "id": "P00748", "database": "UniProt", "url": "" }, { "id": "6QF7", "database": "PDB", "url": "" }, { "id": "P00748", "database": "GeneCards", "url": "" }, { "id": "16010", "database": "Orphanet", "url": "" }, { "id": "4XDE", "database": "PDB", "url": "" }, { "id": "FA12_HUMAN", "database": "ZINC - Investigational", "url": "" }, { "id": "FA12_HUMAN", "database": "ZINC - Predictions - Purchasable", "url": "" }, { "id": "4XE4", "database": "PDB", "url": "" }, { "id": "6SZW", "database": "PDB", "url": "" }, { "id": "4BDW", "database": "PDB", "url": "" }, { "id": "7PRJ", "database": "PDB", "url": "" }, { "id": "2361", "database": "Guide to Pharmacology - Targets", "url": "" }, { "id": "4BDX", "database": "PDB", "url": "" }, { "id": "HMDBP02054", "database": "HMDB Protein", "url": "" }, { "id": "7PRK", "database": "PDB", "url": "" }, { "id": "ENSG00000131187-F12", "database": "HPA", "url": "" }, { "id": "6L63", "database": "PDB", "url": "" }, { "id": "ENSG00000131187", "database": "OpenTargets", "url": "" }, { "id": "6X0T", "database": "PDB", "url": "" }, { "id": "P00748", "database": "Pharos - Targets", "url": "" }, { "id": "6B77", "database": "PDB", "url": "" }, { "id": "FA12_HUMAN", "database": "ZINC - Substances", "url": "" }, { "id": "NP_000496.2", "database": "RefSeq", 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"https://www.uniprot.org/uniprot/P00734" } ] }, { "ec_number": "3.4.21.5", "activity": "", "evidence": [ { "id": "P00734", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P00734" } ] } ] }, { "uniprot_ac": "P00748", "gene_name": "F12", "activity": [ { "ec_number": "3.4.21.38", "activity": "Selective cleavage of Arg-|-Ile bonds in factor VII to form factor VIIa and factor XI to form factor XIa.", "evidence": [ { "id": "P00748", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P00748" } ] }, { "ec_number": "3.4.21.38", "activity": "", "evidence": [ { "id": "P00748", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P00748" } ] } ] }, { "uniprot_ac": "P03951", "gene_name": "F11", "activity": [ { "ec_number": "3.4.21.27", "activity": "Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.", "evidence": [ { "id": "P03951", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P03951" } ] }, { 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