| Structural highlights
Disease
IC1_HUMAN Defects in SERPING1 are the cause of hereditary angioedema (HAE) [MIM:106100; also called hereditary angioneurotic edema (HANE). HAE is an autosomal dominant disorder characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In HAE type 1, representing 85% of patients, serum levels of C1 esterase inhibitor are less than 35% of normal. In HAE type 2, the levels are normal or elevated, but the protein is non-functional.[1] [2] [3] [4] [5] [6] [:][7] [8] [9] [10] [11] [12] [13] [14] [15]
Function
IC1_HUMAN Activation of the C1 complex is under control of the C1-inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein.[16]
Publication Abstract from PubMed
Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertussis, was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8-C1-INH complex determined using cryo-electron microscopy at a 3.6-A resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases.IMPORTANCE The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.
Molecular Basis for Bordetella pertussis Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex.,Dhillon A, Deme JC, Furlong E, Roem D, Jongerius I, Johnson S, Lea SM mBio. 2021 Mar 23;12(2):e02823-20. doi: 10.1128/mBio.02823-20. PMID:33758081[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Verpy E, Couture-Tosi E, Eldering E, Lopez-Trascasa M, Spath P, Meo T, Tosi M. Crucial residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired in secretion or function. J Clin Invest. 1995 Jan;95(1):350-9. PMID:7814636 doi:https://dx.doi.org/10.1172/JCI117663
- ↑ Aulak KS, Pemberton PA, Rosen FS, Carrell RW, Lachmann PJ, Harrison RA. Dysfunctional C1-inhibitor(At), isolated from a type II hereditary-angio-oedema plasma, contains a P1 'reactive centre' (Arg444----His) mutation. Biochem J. 1988 Jul 15;253(2):615-8. PMID:3178731
- ↑ Aulak KS, Cicardi M, Harrison RA. Identification of a new P1 residue mutation (444Arg----Ser) in a dysfunctional C1 inhibitor protein contained in a type II hereditary angioedema plasma. FEBS Lett. 1990 Jun 18;266(1-2):13-6. PMID:2365061
- ↑ Levy NJ, Ramesh N, Cicardi M, Harrison RA, Davis AE 3rd. Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene. Proc Natl Acad Sci U S A. 1990 Jan;87(1):265-8. PMID:2296585
- ↑ Parad RB, Kramer J, Strunk RC, Rosen FS, Davis AE 3rd. Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6786-90. PMID:2118657
- ↑ Frangi D, Aulak KS, Cicardi M, Harrison RA, Davis AE 3rd. A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444-->Leu). FEBS Lett. 1992 Apr 13;301(1):34-6. PMID:1451784
- ↑ Davis AE 3rd, Aulak K, Parad RB, Stecklein HP, Eldering E, Hack CE, Kramer J, Strunk RC, Bissler J, Rosen FS. C1 inhibitor hinge region mutations produce dysfunction by different mechanisms. Nat Genet. 1992 Aug;1(5):354-8. PMID:1363816 doi:https://dx.doi.org/10.1038/ng0892-354
- ↑ Davis AE 3rd, Bissler JJ, Cicardi M. Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema. Behring Inst Mitt. 1993 Dec;(93):313-20. PMID:8172583
- ↑ Zahedi R, Bissler JJ, Davis AE 3rd, Andreadis C, Wisnieski JJ. Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein. J Clin Invest. 1995 Mar;95(3):1299-305. PMID:7883978 doi:https://dx.doi.org/10.1172/JCI117780
- ↑ Ocejo-Vinyals JG, Leyva-Cobian F, Fernandez-Luna JL. A mutation unique in serine protease inhibitors (serpins) identified in a family with type II hereditary angioneurotic edema. Mol Med. 1995 Sep;1(6):700-5. PMID:8529136
- ↑ Verpy E, Biasotto M, Brai M, Misiano G, Meo T, Tosi M. Exhaustive mutation scanning by fluorescence-assisted mismatch analysis discloses new genotype-phenotype correlations in angiodema. Am J Hum Genet. 1996 Aug;59(2):308-19. PMID:8755917
- ↑ Kalmar L, Bors A, Farkas H, Vas S, Fandl B, Varga L, Fust G, Tordai A. Mutation screening of the C1 inhibitor gene among Hungarian patients with hereditary angioedema. Hum Mutat. 2003 Dec;22(6):498. PMID:14635117 doi:10.1002/humu.9202
- ↑ Kang HR, Yim EY, Oh SY, Chang YS, Kim YK, Cho SH, Min KU, Kim YY. Normal C1 inhibitor mRNA expression level in type I hereditary angioedema patients: newly found C1 inhibitor gene mutations. Allergy. 2006 Feb;61(2):260-4. PMID:16409206 doi:10.1111/j.1398-9995.2006.01010.x
- ↑ Xu YY, Zhi YX, Yin J, Wang LL, Wen LP, Gu JQ, Guan K, Craig T, Zhang HY. Mutational spectrum and geno-phenotype correlation in Chinese families with hereditary angioedema. Allergy. 2012 Nov;67(11):1430-6. doi: 10.1111/all.12024. Epub 2012 Sep 21. PMID:22994404 doi:10.1111/all.12024
- ↑ Aulak KS, Davis AE 3rd, Donaldson VH, Harrison RA. Chymotrypsin inhibitory activity of normal C1-inhibitor and a P1 Arg to His mutant: evidence for the presence of overlapping reactive centers. Protein Sci. 1993 May;2(5):727-32. PMID:8495195 doi:https://dx.doi.org/10.1002/pro.5560020504
- ↑ Dhillon A, Deme JC, Furlong E, Roem D, Jongerius I, Johnson S, Lea SM. Molecular Basis for Bordetella pertussis Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex. mBio. 2021 Mar 23;12(2):e02823-20. PMID:33758081 doi:10.1128/mBio.02823-20
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