complement c1s


Summary: A 77-kDa subcomponent of complement C1, encoded by gene C1S, is a SERINE PROTEASE existing as a proenzyme (homodimer) in the intact complement C1 complex. Upon the binding of COMPLEMENT C1Q to antibodies, the activated COMPLEMENT C1R cleaves C1s into two chains, A (heavy) and B (light, the serine protease), linked by disulfide bonds yielding the active C1s. The activated C1s, in turn, cleaves COMPLEMENT C2 and COMPLEMENT C4 to form C4b2a (CLASSICAL C3 CONVERTASE).

Top Publications

  1. Gaboriaud C, Rossi V, Bally I, Arlaud G, Fontecilla Camps J. Crystal structure of the catalytic domain of human complement c1s: a serine protease with a handle. EMBO J. 2000;19:1755-65 pubmed
    ..This structure provides a first example of a CCP-SP assembly that is conserved in diverse extracellular proteins. Its implications in the activation mechanism of C1 are discussed. ..
  2. Harmat V, Gal P, Kardos J, Szilágyi K, Ambrus G, Végh B, et al. The structure of MBL-associated serine protease-2 reveals that identical substrate specificities of C1s and MASP-2 are realized through different sets of enzyme-substrate interactions. J Mol Biol. 2004;342:1533-46 pubmed
  3. Amano M, Ferriani V, Florido M, Reis E, Delcolli M, Azzolini A, et al. Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene. Mol Immunol. 2008;45:1693-702 pubmed
    ..These variants are derived from the skipping of exon 3 and from the use of an alternative 3' splice site within intron 1 which increases the size of exon 2 by 87 nucleotides. ..
  4. Gaboriaud C, Thielens N, Gregory L, Rossi V, Fontecilla Camps J, Arlaud G. Structure and activation of the C1 complex of complement: unraveling the puzzle. Trends Immunol. 2004;25:368-73 pubmed
  5. Sakai H, Nakashima S, Yoshimura S, Nishimura Y, Sakai N, Nozawa Y. Molecular cloning of a cDNA encoding a serine protease homologous to complement C1s precursor from rat C6 glial cells and its expression during glial differentiation. Gene. 1998;209:87-94 pubmed
    ..isolated by mRNA fingerprinting using arbitrarily primed polymerase chain reaction, and was homologous to complement C1s precursors of hamster and human...
  6. Thielens N, Cseh S, Thiel S, Vorup Jensen T, Rossi V, Jensenius J, et al. Interaction properties of human mannan-binding lectin (MBL)-associated serine proteases-1 and -2, MBL-associated protein 19, and MBL. J Immunol. 2001;166:5068-77 pubmed
    ..This suggests that distinct MBL/MASP complexes may be involved in the activation or regulation of the MBL pathway. ..
  7. Veerhuis R, Janssen I, De Groot C, van Muiswinkel F, Hack C, Eikelenboom P. Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor. Exp Neurol. 1999;160:289-99 pubmed
  8. Subasinghe N, Travins J, Ali F, Huang H, Ballentine S, Marugan J, et al. A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s. Bioorg Med Chem Lett. 2006;16:2200-4 pubmed
    ..The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin. ..
  9. Skoog M, Mehdi S, Wiseman J, Bey P. The specificity of two proteinases that cleave adjacent to arginine, C1 esterase and acrosin, for peptide p-nitroanilide substrates. Biochim Biophys Acta. 1989;996:89-94 pubmed
    ..Thus, an acrosin assay using Tos-Gly-Pro-Arg p-nitroanilide as a substrate is more than 20-times as sensitive as existing assays with blocked arginine derivatives. ..

More Information


  1. Laurell A, Martensson U, Sjoholm A. C1 dissociation. Spontaneous generation in human serum of a trimer complex containing C1 inactivator, activated C1r, and zymogen C1s. J Immunol. 1987;139:4145-51 pubmed
    ..Consistent with results obtained by size exclusion chromatography, analysis by crossed immunoelectrophoresis and by electroimmunoassay showed that C1s could be released from C1 IA-C1r-C1s in the presence of EDTA. ..
  2. Carroll S, Georgiou G. Antibody-mediates inhibition of human C1s and the classical complement pathway. Immunobiology. 2013;218:1041-8 pubmed publisher
    ..C1s inhibitory antibodies should be useful for delineating the role of the classical pathway in disease models and may hold promise as therapeutic agents. ..
  3. Rossi V, Gaboriaud C, Lacroix M, Ulrich J, Fontecilla Camps J, Gagnon J, et al. Structure of the catalytic region of human complement protease C1s: study by chemical cross-linking and three-dimensional homology modeling. Biochemistry. 1995;34:7311-21 pubmed
    ..Functional implications of this interaction are discussed in terms of the possible role of module V in the specific recognition and positioning of C4, one of the two substrates of C1s. ..
  4. Takayama Y, Takada F, Nowatari M, Kawakami M, Matsu ura N. Gene structure of the P100 serine-protease component of the human Ra-reactive factor. Mol Immunol. 1999;36:505-14 pubmed
    ..The exon-intron structure was found to reflect the evolution of these molecules and P100 to have derived earlier in the stage of evolution than C1r or C1s. ..
  5. Thielens N, Van Dorsselaer A, Gagnon J, Arlaud G. Chemical and functional characterization of a fragment of C1-s containing the epidermal growth factor homology region. Biochemistry. 1990;29:3570-8 pubmed
    ..abstract truncated at 250 words) ..
  6. Laubinger R, Guthke K, Erdmann U, Klein U. [Angioneurotic orolingual edema associated with the use of rt-PA following a stroke]. Anaesthesist. 2007;56:1024-7 pubmed
    ..It was possible to avoid intubation and ventilation in both cases. Therapy with ranitidine, clemastine, and a C1 esterase inhibitor resulted in the resolution of symptomatic angioneurotic edema within hours. ..
  7. Bernstein J, Manning M, Li H, White M, Baker J, Lumry W, et al. Escalating doses of C1 esterase inhibitor (CINRYZE) for prophylaxis in patients with hereditary angioedema. J Allergy Clin Immunol Pract. 2014;2:77-84 pubmed publisher
    ..0/month. Dose escalation of nanofiltered C1 inhibitor (human) up to 2500 U was well tolerated and reduced attack frequency in the majority of patients. ..
  8. Tissot B, Montdargent B, Chevolot L, Varenne A, Descroix S, Gareil P, et al. Interaction of fucoidan with the proteins of the complement classical pathway. Biochim Biophys Acta. 2003;1651:5-16 pubmed
  9. Davis A, Aulak K, Parad R, Stecklein H, Eldering E, Hack C, et al. C1 inhibitor hinge region mutations produce dysfunction by different mechanisms. Nat Genet. 1992;1:354-8 pubmed
    ..The two mutations, therefore, result in dysfunction by different mechanisms: in one (P14 Val-->Glu), the inhibitor is converted to a substrate, while in the other (P10 Ala-->Thr), interaction with target protease is blocked. ..
  10. Lawson P, Reid K. A novel PCR-based technique using expressed sequence tags and gene homology for murine genetic mapping: localization of the complement genes. Int Immunol. 2000;12:231-40 pubmed
    ..These results provide new insights into the evolution of this group of proteins. ..
  11. Thielens N, Aude C, Lacroix M, Gagnon J, Arlaud G. Ca2+ binding properties and Ca2(+)-dependent interactions of the isolated NH2-terminal alpha fragments of human complement proteases C1-r and C1-s. J Biol Chem. 1990;265:14469-75 pubmed
    ..This 1:1 stoichiometry is maintained upon heterologous (C1-r-C1-s) interaction, whereas the homologous (C1-s-C1-s) interaction provides one additional binding site. ..
  12. Endo Y, Sato T, Matsushita M, Fujita T. Exon structure of the gene encoding the human mannose-binding protein-associated serine protease light chain: comparison with complement C1r and C1s genes. Int Immunol. 1996;8:1355-8 pubmed
  13. Katz Y, Strunk R. Synthesis and regulation of C1 inhibitor in human skin fibroblasts. J Immunol. 1989;142:2041-5 pubmed
    ..In addition, fibroblasts should be a good model for the in vitro study of genetic diseases involving the synthesis of these proteins. ..
  14. Spycher S, Nick H, Rickli E. Human complement component C1s. Partial sequence determination of the heavy chain and identification of the peptide bond cleaved during activation. Eur J Biochem. 1986;156:49-57 pubmed
    ..The sequence data and homology to two-chain serine proteases indicate a single interchain disulfide bond in C1s. ..
  15. Gabrielsson B, Johansson J, Lönn M, Jernas M, Olbers T, Peltonen M, et al. High expression of complement components in omental adipose tissue in obese men. Obes Res. 2003;11:699-708 pubmed
  16. Wellwood J, Taylor K, Wright S, Bentley M, Eliadis P. Angioedema in the emergency department: a presentation of lymphoma. Emerg Med (Fremantle). 2001;13:465-8 pubmed
    ..Resolution of the angioedema and C1 esterase inhibitor deficiency was achieved with danazol and treatment of the underlying lymphoma. ..
  17. Langlois P, Gawryl M. Complement activation occurs through both classical and alternative pathways prior to onset and resolution of adult respiratory distress syndrome. Clin Immunol Immunopathol. 1988;47:152-63 pubmed
    ..02) and also with C3bP complex (r = 0.72, P = 0.002) levels. Our results indicate that both the classical and alternative complement pathways are activated prior to onset of ARDS and also before its resolution in septic patients. ..
  18. Davis A. Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol. 2008;100:S7-12 pubmed
    ..Hereditary angioedema attacks are mediated by bradykinin generated via contact system activation. The specific factors that trigger attacks remain unclear. ..
  19. Tei R, Kaido T, Nakase H, Sakaki T. Protective effect of C1 esterase inhibitor on acute traumatic spinal cord injury in the rat. Neurol Res. 2008;30:761-7 pubmed publisher
    ..05). The results of this study provided the first evidence that C1-INH reduced accumulation of polymorphonuclear leukocytes (PMLs) and neuronal damage in acute stage after SCI. This protection was not related to an improvement in rSCBF. ..
  20. Gal P, Dobó J, Zavodszky P, Sim R. Early complement proteases: C1r, C1s and MASPs. A structural insight into activation and functions. Mol Immunol. 2009;46:2745-52 pubmed publisher
    ..We also discuss some open questions and debated issues that need to be resolved in the future. ..
  21. Brier S, Pflieger D, Le Mignon M, Bally I, Gaboriaud C, Arlaud G, et al. Mapping surface accessibility of the C1r/C1s tetramer by chemical modification and mass spectrometry provides new insights into assembly of the human C1 complex. J Biol Chem. 2010;285:32251-63 pubmed publisher
    ..These results provide further structural insights into the architecture of the C1 complex, allowing significant improvement of our current C1 model. ..
  22. van Kilsdonk J, Takahashi N, Weidle U, Burtscher H, Jarry J, Daha M, et al. Modulation of activated leukocyte cell adhesion molecule-mediated invasion triggers an innate immune gene response in melanoma. J Invest Dermatol. 2012;132:1462-70 pubmed publisher
    ..Together, our results demonstrate a link between ALCAM functionality and the immune transcriptome, and support the assumption that ALCAM-ALCAM interactions could function as a cell signaling complex to promote melanoma tumor invasion. ..
  23. O Brien G, Quinsey N, Whisstock J, Pike R. Importance of the prime subsites of the C1s protease of the classical complement pathway for recognition of substrates. Biochemistry. 2003;42:14939-45 pubmed
  24. Medved L, Busby T, Ingham K. Calorimetric investigation of the domain structure of human complement Cl-s: reversible unfolding of the short consensus repeat units. Biochemistry. 1989;28:5408-14 pubmed
    ..Cl-s-gamma exhibits a reversible transition near 60 degrees C corresponding to the highest temperature peak in whole Cl-s and Cl-s-A.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  25. Beveridge A, Wallis R, Samani N. A molecular dynamics study of C1r and C1s dimers: implications for the structure of the C1 complex. Proteins. 2012;80:1987-97 pubmed publisher
    ..Furthermore, it identifies a number of putative binding residues that can be tested using site-directed mutagenesis. ..
  26. De Agostini A, Patston P, Marottoli V, Carrel S, Harpel P, Schapira M. A common neoepitope is created when the reactive center of C1-inhibitor is cleaved by plasma kallikrein, activated factor XII fragment, C1 esterase, or neutrophil elastase. J Clin Invest. 1988;82:700-5 pubmed
    ..In the study reported here, we show, using an MAb, that an identical neoepitope is created on C1-inhibitor after the cleavage of its exposed loop by plasma kallikrein, C1s, beta-Factor XIIa, and by neutrophil elastase. ..
  27. Gal P, Ambrus G, Zavodszky P. C1s, the protease messenger of C1. Structure, function and physiological significance. Immunobiology. 2002;205:383-94 pubmed
    ..The results obtained by genetic engineering, physico-chemical and functional studies are reviewed. The physiological relevance of the proteolytic action of C1s and its possible implications in health and disease will also be discussed. ..
  28. Chesne S, Villiers C, Arlaud G, Lacroix M, Colomb M. Fluid-phase interaction of C1 inhibitor (C1 Inh) and the subcomponents C1r and C1s of the first component of complement, C1. Biochem J. 1982;201:61-70 pubmed
    ..5) or totally (pH 9.0) when the incubation was performed in denaturing conditions. An ester link between a serine residue at the active site of C1r or C1s and C1 Inh is postulated. ..
  29. Bradley K, North J, Saunders D, Schwaeble W, Jeziorska M, Woolley D, et al. Synthesis of classical pathway complement components by chondrocytes. Immunology. 1996;88:648-56 pubmed
    ..The possible roles of local synthesis of complement components by chondrocytes in matrix turnover and the regulation chondrocyte function are discussed. ..
  30. Busby T, Ingham K. Domain structure, stability, and interactions of human complement C1s-: characterization of a derivative lacking most of the B chain. Biochemistry. 1988;27:6127-35 pubmed
    ..They also provide direct proof for the occurrence of Ca2+ binding sites on the A chain and demonstrate that all or most of the sites on C1-s that are responsible for its interaction with C1-r and C1q are located on the A chain. ..
  31. Lyons L, Kamboh M, Ferrell R. Genetic studies of low-abundance human plasma proteins. XI. Linkage analysis and population genetics of the C1S subcomponent of the first complement component. Complement Inflamm. 1989;6:81-7 pubmed
    ..In addition, the product of a putative new allele, designated C1S*4, was observed in a single US White individual but segregation of this variant was not observed in the limited family data available. ..
  32. Watford W, Wright J, Hester C, Jiang H, Frank M. Surfactant protein A regulates complement activation. J Immunol. 2001;167:6593-600 pubmed
    ..We hypothesize that SP-A may serve a protective role in the lung by preventing C1q-mediated complement activation and inflammation along the delicate alveolar epithelium. ..
  33. Zhang J, Wright W, Bernlohr D, Cushman S, Chen X. Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2007;292:E1433-40 pubmed
    ..Our findings also demonstrate that excessive activation of the classic pathway of complement commonly occurs in obesity, suggesting its possible role in adipose tissue inflammation and insulin resistance. ..
  34. Bos I, van Mierlo G, Bleeker W, Rigter G, te Velthuis H, Dickneite G, et al. The potentiation of human C1-inhibitor by dextran sulphate is transient in vivo: studies in a rat model. Int Immunopharmacol. 2001;1:1583-95 pubmed
    ..Hence, co-administration of these compounds seems a feasible approach to achieve short-term inhibition of complement in vivo. ..
  35. Hsiung L, Dodds A, Mason D, Reid K. A monoclonal antibody to C1q which appears to interact with C1r2C1s2-binding site. FEBS Lett. 1988;229:21-4 pubmed
    ..This indicates that the binding of the antibody to the collagenous portion of the B chain of C1q probably prevents interaction between C1q and the C1r2-C1s2 complex. ..
  36. Takayama Y, Takada F, Takahashi A, Kawakami M. A 100-kDa protein in the C4-activating component of Ra-reactive factor is a new serine protease having module organization similar to C1r and C1s. J Immunol. 1994;152:2308-16 pubmed
    ..Northern hybridization showed that the liver was the primary site of the expression of the P100 gene. ..
  37. Nonaka M, Azumi K. Opsonic complement system of the solitary ascidian, Halocynthia roretzi. Dev Comp Immunol. 1999;23:421-7 pubmed
    ..These results indicate that the lectin-dependent, opsonic complement system was present prior to the emergence of the vertebrates and well ahead of the establishment of adaptive immunity. ..
  38. Cseh S, Vera L, Matsushita M, Fujita T, Arlaud G, Thielens N. Characterization of the interaction between L-ficolin/p35 and mannan-binding lectin-associated serine proteases-1 and -2. J Immunol. 2002;169:5735-43 pubmed
    ..Preincubation of the MASPs with soluble MBL inhibited subsequent binding to immobilized L-ficolin/P35 and, conversely, suggesting that these lectins compete with each other for binding to the MASPs in vivo. ..
  39. Przysiecki C, Staggers J, Ramjit H, Musson D, Stern A, Bennett C, et al. Occurrence of beta-hydroxylated asparagine residues in non-vitamin K-dependent proteins containing epidermal growth factor-like domains. Proc Natl Acad Sci U S A. 1987;84:7856-60 pubmed
    ..Based upon available cDNA sequence data and observation of e-beta Hya in acid hydrolysates, we suggest other proteins in which e-beta Hyn may occur. ..
  40. Venkatraman Girija U, Gingras A, Marshall J, Panchal R, Sheikh M, Harper J, et al. Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation. Proc Natl Acad Sci U S A. 2013;110:13916-20 pubmed publisher
    ..Together with previously determined structures of C1r fragments, the results reported here provide a structural basis for understanding the early steps of complement activation via the classical pathway. ..
  41. Jackson J, Sim R, Whaley K, Feighery C. Autoantibody facilitated cleavage of C1-inhibitor in autoimmune angioedema. J Clin Invest. 1989;83:698-707 pubmed
    ..These findings contribute to our understanding of protease/C1-Inh interactions and document important observations on pathogenic mechanisms in autoimmune disease. ..
  42. Naito A, Sumida T, Nomura S, Liu M, Higo T, Nakagawa A, et al. Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes. Cell. 2012;149:1298-313 pubmed publisher
    ..Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging. ..
  43. Pflieger D, Przybylski C, Gonnet F, Le Caer J, Lunardi T, Arlaud G, et al. Analysis of human C1q by combined bottom-up and top-down mass spectrometry: detailed mapping of post-translational modifications and insights into the C1r/C1s binding sites. Mol Cell Proteomics. 2010;9:593-610 pubmed publisher
    ..They are thus fully available and in an appropriate position to interact with the C1r and C1s protease partners of C1q and are therefore likely to play an essential role in C1 assembly. ..
  44. Krishnan V, Xu Y, Macon K, Volanakis J, Narayana S. The structure of C2b, a fragment of complement component C2 produced during C3 convertase formation. Acta Crystallogr D Biol Crystallogr. 2009;65:266-74 pubmed publisher
    ..The results of this study also suggest that upon cleavage by C1s, C2a domains undergo conformational rotation while bound to C4b and the released C2b domains may remain folded together similar to as observed in the intact protein. ..
  45. Bally I, Ancelet S, Moriscot C, Gonnet F, Mantovani A, Daniel R, et al. Expression of recombinant human complement C1q allows identification of the C1r/C1s-binding sites. Proc Natl Acad Sci U S A. 2013;110:8650-5 pubmed publisher
    ..The expression method reported here opens the way for deciphering the molecular basis of the unusual binding versatility of C1q by mapping the residues involved in the sensing of its targets and the binding of its receptors. ..
  46. Thielens N, Enrie K, Lacroix M, Jaquinod M, Hernandez J, Esser A, et al. The N-terminal CUB-epidermal growth factor module pair of human complement protease C1r binds Ca2+ with high affinity and mediates Ca2+-dependent interaction with C1s. J Biol Chem. 1999;274:9149-59 pubmed
  47. Kurita M, Matsumoto M, Tsuji S, Kawakami M, Suzuki Y, Hayashi H, et al. Antibody-independent classical complement pathway activation and homologous C3 deposition in xeroderma pigmentosum cell lines. Clin Exp Immunol. 1999;116:547-53 pubmed
    ..The possible relationship between the pathogenesis of XP and our findings is discussed. ..
  48. Inal J, Schifferli J. Complement C2 receptor inhibitor trispanning and the beta-chain of C4 share a binding site for complement C2. J Immunol. 2002;168:5213-21 pubmed
    ..These peptides, based on C2-binding sequences in CRIT, or C4, competitively inhibit the binding of C2 to C4b and thus limit the activation of C. The C4 peptides, unlike CRIT-ed1, did not inhibit the cleavage of C2 by C1s. ..
  49. Stiefelhagen P. [Colic-like abdominal pain and edema in a young woman. Cause of complaints was not in the abdomen]. MMW Fortschr Med. 2006;148:13-4 pubmed
  50. Lee H, Mendes F, Plouhinec J, De Robertis E. Enzymatic regulation of pattern: BMP4 binds CUB domains of Tolloids and inhibits proteinase activity. Genes Dev. 2009;23:2551-62 pubmed publisher
    ..Mathematical modeling indicates that feedback inhibition by BMP ligands acts on the ventral side, while on the dorsal side the main regulator of BMP1/Tolloid enzymatic activity is the binding to its substrate, Chordin. ..
  51. Endo Y, Takahashi M, Kuraya M, Matsushita M, Stover C, Schwaeble W, et al. Functional characterization of human mannose-binding lectin-associated serine protease (MASP)-1/3 and MASP-2 promoters, and comparison with the C1s promoter. Int Immunol. 2002;14:1193-201 pubmed
  52. Vorup Jensen T, Jensenius J, Thiel S. MASP-2, the C3 convertase generating protease of the MBLectin complement activating pathway. Immunobiology. 1998;199:348-57 pubmed
    ..Phylogenetic analysis indicates that MASP-2 is closer to C1r and C1s than is MASP-1, but no particular association between MASP-2 and the C4 cleaving enzyme, C1s, can be deduced from sequence comparison. ..
  53. Clemmons D, Busby W, Garmong A, Schultz D, Howell D, Altman R, et al. Inhibition of insulin-like growth factor binding protein 5 proteolysis in articular cartilage and joint fluid results in enhanced concentrations of insulin-like growth factor 1 and is associated with improved osteoarthritis. Arthritis Rheum. 2002;46:694-703 pubmed
    ..This increase in concentrations of intact IGFBP-3 and IGFBP-5 leads to an increase in IGF-1 which is associated with an improvement in joint architecture during the development of OA. ..