complement c1r


Summary: A 80-kDa subcomponent of complement C1, existing as a SERINE PROTEASE proenzyme in the intact complement C1 complex. When COMPLEMENT C1Q is bound to antibodies, the changed tertiary structure causes autolytic activation of complement C1r which is cleaved into two chains, A (heavy) and B (light, the serine protease), connected by disulfide bonds. The activated C1r serine protease, in turn, activates COMPLEMENT C1S proenzyme by cleaving the Arg426-Ile427 bond. No fragment is released when either C1r or C1s is cleaved.

Top Publications

  1. Budayova Spano M, Lacroix M, Thielens N, Arlaud G, Fontecilla Camps J, Gaboriaud C. The crystal structure of the zymogen catalytic domain of complement protease C1r reveals that a disruptive mechanical stress is required to trigger activation of the C1 complex. EMBO J. 2002;21:231-9 pubmed
  2. Budayova Spano M, Grabarse W, Thielens N, Hillen H, Lacroix M, Schmidt M, et al. Monomeric structures of the zymogen and active catalytic domain of complement protease c1r: further insights into the c1 activation mechanism. Structure. 2002;10:1509-19 pubmed
    ..Further implications relevant to the C1r self-activation process are derived from protein-protein interactions in the crystals. ..
  3. 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
  4. Kerényi A, Nagy G, Veres A, Varga L, Füst A, Nagymihány A, et al. C1r-C1s-C1inhibitor (C1rs-C1inh) complex measurements in tears of patients before and after penetrating keratoplasty. Curr Eye Res. 2002;24:99-104 pubmed
    ..These findings provide direct evidence that the classical pathway of complement may be activated in the early postoperative period after penetrating keratoplasty. ..
  5. Lacroix M, Ebel C, Kardos J, Dobó J, Gal P, Zavodszky P, et al. Assembly and enzymatic properties of the catalytic domain of human complement protease C1r. J Biol Chem. 2001;276:36233-40 pubmed
    ..C1r and its activated fragments all cleaved C1s, with relative efficiencies in the order C1r < CCP1/2-SP < CCP2-SP, indicating that CCP1 is not involved in C1s recognition. ..
  6. 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
  7. Wicher K, Fries E. Prohaptoglobin is proteolytically cleaved in the endoplasmic reticulum by the complement C1r-like protein. Proc Natl Acad Sci U S A. 2004;101:14390-5 pubmed
    ..Here, we present evidence that the recently discovered complement C1r-like protein (C1r-LP) mediates this cleavage...
  8. 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
  9. Leytus S, Kurachi K, Sakariassen K, Davie E. Nucleotide sequence of the cDNA coding for human complement C1r. Biochemistry. 1986;25:4855-63 pubmed
    ..The B chain of C-1r contains the catalytic portion of the enzyme and is homologous to the trypsin family of serine proteases. ..

More Information


  1. Endo Y, Nonaka M, Saiga H, Kakinuma Y, Matsushita A, Takahashi M, et al. Origin of mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 involved in the lectin complement pathway traced back to the invertebrate, amphioxus. J Immunol. 2003;170:4701-7 pubmed
    ..The ancient origin of MASP-1 and MASP-3 suggests that they have crucial functions common to all species which emerged after cephalochordates. ..
  2. Moralez A, Busby W, Clemmons D. Control of insulin-like growth factor binding protein-5 protease synthesis and secretion by human fibroblasts and porcine aortic smooth muscle cells. Endocrinology. 2003;144:2489-95 pubmed
    ..This increase results in a net increase in IGFBP-5 proteolysis, which has the potential to modify IGF-I and IGFBP-5 actions. ..
  3. Kardos J, Harmat V, Palló A, Barabas O, Szilágyi K, Gráf L, et al. Revisiting the mechanism of the autoactivation of the complement protease C1r in the C1 complex: structure of the active catalytic region of C1r. Mol Immunol. 2008;45:1752-60 pubmed
    ..It allows autoactivation of C1r without large-scale, directed movement of C1q arms. The model is concordant with the stability of the C1 complex during activation of the next complement components. ..
  4. 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. ..
  5. Watanabe A, Satoh K, Maniwa T, Matsumoto K. Proteomic analysis for the identification of serum diagnostic markers for joint hypermobility syndrome. Int J Mol Med. 2016;37:461-7 pubmed publisher
    ..05, patient vs. control). Of the 6 proteins, proteins involved in the complement system including complement C1r subcomponent (C1R), vitronectin (VTN), complement component C9 (C9), and C4b-binding protein alpha chain (..
  6. Füst A, Csuka D, Suveges I, Imre L, Bausz M, Nagymihály A, et al. Complement activation in the aqueous humor of pseudophakic bullous keratopathy patients. Ophthalmic Res. 2013;49:161-6 pubmed publisher
    ..Our new findings indicate that in PBK the complement system is activated - via the classical pathway - in the aqueous humor. The activated complement may play a role in increased endothelial cell loss. ..
  7. Kamboh M, Lyons L, Ferrell R. Genetic studies of low-abundance human plasma proteins. XIII. Population genetics of C1R complement subcomponent and description of new variants. Am J Hum Genet. 1989;44:148-53 pubmed
    ..03 to .17, in all of the North American aboriginal populations screened. This allele is not present in U.S. whites but is present at a polymorphic frequency in U.S. and Nigerian blacks.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  8. Bally I, Rossi V, Lunardi T, Thielens N, Gaboriaud C, Arlaud G. Identification of the C1q-binding Sites of Human C1r and C1s: a refined three-dimensional model of the C1 complex of complement. J Biol Chem. 2009;284:19340-8 pubmed publisher
    ..This mechanism is similar to that demonstrated for mannan-binding lectin (MBL)-MBL-associated serine protease and ficolin-MBL-associated serine protease complexes. ..
  9. Luo C, Thielens N, Gagnon J, Gal P, Sarvari M, Tseng Y, et al. Recombinant human complement subcomponent C1s lacking beta-hydroxyasparagine, sialic acid, and one of its two carbohydrate chains still reassembles with C1q and C1r to form a functional C1 complex. Biochemistry. 1992;31:4254-62 pubmed
    ..A very tight complex is formed between C1-inhibitor and the light chain of recombinant C1s.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  10. Prellner K, Sjoholm A, Truedsson L. Concentrations of C1q, factor B, factor D and properdin in healthy children, and the age-related presence of circulating C1r-C1s complexes. Acta Paediatr Scand. 1987;76:939-43 pubmed
    ..Since the concentrations of C1q are influenced by those of IgG, the presence of C1r-C1s complexes might partly have reflected maturation of immunoglobulin synthesis during ontogeny. ..
  11. Nakagawa M, Nakashima S, Banno Y, Yamada J, Sawada M, Yoshimura S, et al. Increased expression and secretion of r-Gsp protein, rat counterpart of complement C1s precursor, during cyclic AMP-induced differentiation in rat C6 glioma cells. Brain Res Mol Brain Res. 2002;106:12-21 pubmed
    ..Its possible role in glial cell differentiation will be discussed. ..
  12. Lacroix M, Rossi V, Gaboriaud C, Chevallier S, Jaquinod M, Thielens N, et al. Structure and assembly of the catalytic region of human complement protease C1r: a three-dimensional model based on chemical cross-linking and homology modeling. Biochemistry. 1997;36:6270-82 pubmed
    ..The latter model is compared with available low-resolution structural data, and its functional implications are discussed in terms of the conformational changes occurring during C1r activation. ..
  13. Bersch B, Hernandez J, Marion D, Arlaud G. Solution structure of the epidermal growth factor (EGF)-like module of human complement protease C1r, an atypical member of the EGF family. Biochemistry. 1998;37:1204-14 pubmed
    ..Additional experiments in the presence of 80 mM Ca2+ did not show significant structural variation of C1r-EGF, in keeping with previous observations on blood-clotting factors IX and X. ..
  14. Kusumoto H, Hirosawa S, Salier J, Hagen F, Kurachi K. Human genes for complement components C1r and C1s in a close tail-to-tail arrangement. Proc Natl Acad Sci U S A. 1988;85:7307-11 pubmed
    ..Multiple molecular sizes of specific mRNAs were observed in the RNA blot analyses for both C1r and C1s, indicating that alternative RNA processing(s), likely an alternative polyadenylylation, might take place for both genes. ..
  15. Wu Y, Brookshire B, Verani R, Arnett F, Yu C. Clinical presentations and molecular basis of complement C1r deficiency in a male African-American patient with systemic lupus erythematosus. Lupus. 2011;20:1126-34 pubmed publisher
    ..Screening of 209 African-American SLE patients suggested that the R380X mutation is a rare causal variant. Mutations leading to early complement component deficiencies in SLE are mostly private variants with large effects. ..
  16. Calamia V, Lourido L, Fernández Puente P, Mateos J, Rocha B, Montell E, et al. Secretome analysis of chondroitin sulfate-treated chondrocytes reveals anti-angiogenic, anti-inflammatory and anti-catabolic properties. Arthritis Res Ther. 2012;14:R202 pubmed publisher
    ..We have also provided novel evidences of its anti-angiogenic, anti-inflammatory, and anti-catabolic properties. Demonstration of the anti-angiogenic action of CS might provide a novel therapeutic approach for OA targeting. ..
  17. Lacroix M, Aude C, Arlaud G, Colomb M. Isolation and functional characterization of the proenzyme form of the catalytic domains of human C1r. Biochem J. 1989;257:885-91 pubmed
  18. Arlaud G, Gaboriaud C, Thielens N, Rossi V, Bersch B, Hernandez J, et al. Structural biology of C1: dissection of a complex molecular machinery. Immunol Rev. 2001;180:136-45 pubmed
  19. Lin N, Liu S, Li N, Wu P, An H, Yu Y, et al. A novel human dendritic cell-derived C1r-like serine protease analog inhibits complement-mediated cytotoxicity. Biochem Biophys Res Commun. 2004;321:329-36 pubmed
    ..It shares great homology with complement C1r/C1s and mannose-associated serine proteases...
  20. Ellison R, Curd J, Kohler P, Reller L, Judson F. Underlying complement deficiency in patients with disseminated gonococcal infection. Sex Transm Dis. 1987;14:201-4 pubmed
  21. 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
  22. Busby T, Ingham K. Calcium-sensitive thermal transitions and domain structure of human complement subcomponent C1r. Biochemistry. 1987;26:5564-71 pubmed
    ..Addition of Ca2+ stabilizes this fragment, shifting the midpoint of its melting transition upward by more than 20 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  23. Hernandez J, Bersch B, Petillot Y, Gagnon J, Arlaud G. Chemical synthesis and characterization of the epidermal growth factor-like module of human complement protease C1r. J Pept Res. 1997;49:221-31 pubmed
    ..As already proposed for factors IX and X, it is suggested that neighbouring module(s), most probably the N-terminal CUB module, contribute(s) to the calcium binding site. ..
  24. Láng A, Szilágyi K, Major B, Gal P, Zavodszky P, Perczel A. Intermodule cooperativity in the structure and dynamics of consecutive complement control modules in human C1r: structural biology. FEBS J. 2010;277:3986-98 pubmed publisher
    ..Therefore, CCP1 could be a focal interaction point, capable of transmitting information towards its neighboring modules. ..
  25. Füst A, Csuka D, Imre L, Bausz M, Nagymihály A, Fust G, et al. The role of complement activation in the pathogenesis of Fuchs' dystrophy. Mol Immunol. 2014;58:177-81 pubmed publisher
    ..Based on our results, the complement system may be activated both through the classical and alternative pathways in the aqueous humor of the patients with Fuchs' dystrophy. ..
  26. Krishna N, Cunnion K. Human astrovirus coat protein: a novel C1 inhibitor. Adv Exp Med Biol. 2008;632:237-51 pubmed
    ..Additionally, the properties of this compound are elucidated highlighting its potential as an anti-complement therapeutic for the many diseases associated with inappropriate complement activation. ..
  27. Kim M, Oh J, Ko J, Lee H, Jung J, Wee W, et al. DNA microarray-based gene expression profiling in porcine keratocytes and corneal endothelial cells and comparative analysis associated with xeno-related rejection. J Korean Med Sci. 2009;24:189-96 pubmed publisher
    ..In conclusion, the increased expression of C1R, CCL2, and HLA-A genes in porcine keratocytes might be responsible for the stromal rejection observed in a porcine to rat corneal xenotransplantation. ..
  28. Demirkaya E, Zhou Q, Smith C, Ombrello M, Deuitch N, Tsai W, et al. Brief Report: Deficiency of Complement 1r Subcomponent in Early-Onset Systemic Lupus Erythematosus: The Role of Disease-Modifying Alleles in a Monogenic Disease. Arthritis Rheumatol. 2017;69:1832-1839 pubmed publisher
    ..Our findings revealed a novel high-penetrance mutation in C1R as the cause of monogenic SLE. Disease expressivity in this family appears to be influenced by additional common and rare genetic variants. ..
  29. 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) ..
  30. Jack R, Fearon D. Selective synthesis of mRNA and proteins by human peripheral blood neutrophils. J Immunol. 1988;140:4286-93 pubmed
    ..In contrast, the lack of detectable synthesis of either lactoferrin or CR3 beta-chain suggested that biosynthesis in circulating PMN is selective. ..
  31. Thiel S, Petersen S, Vorup Jensen T, Matsushita M, Fujita T, Stover C, et al. Interaction of C1q and mannan-binding lectin (MBL) with C1r, C1s, MBL-associated serine proteases 1 and 2, and the MBL-associated protein MAp19. J Immunol. 2000;165:878-87 pubmed
    ..Over 95% of the total MASPs and MAp19 found in serum are not complexed with MBL. ..
  32. Hidvegi T, Ermolin G, Efremov E, Dikov M, Kurmanova L, Vnashenkova G, et al. FN-C1q and C1 INH C1r-C1s complexes as indicators of complement activation in patients with chronic lymphocytic leukaemia. Immunol Lett. 1989;22:1-6 pubmed
    ..These findings support the assumption that the classical complement pathway is activated in the patients with CLL. ..
  33. 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. ..
  34. 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. ..
  35. Peitsch M, Kovacsovics T, Isliker H. A rapid and efficient method for the purification of the complement subcomponents C1r and C1s in zymogen form using fast protein chromatography. J Immunol Methods. 1988;108:265-9 pubmed
    ..The method provides C1r and C1s in a yield of 35 and 60% respectively. In addition, this study provides a simple and sensitive test to assess functional purity of C1r and C1s with respect to the other C1 subcomponents. ..
  36. Nguyen V, Tosi M, Gross M, Cohen Haguenauer O, Jegou Foubert C, de Tand M, et al. Assignment of the complement serine protease genes C1r and C1s to chromosome 12 region 12p13. Hum Genet. 1988;78:363-8 pubmed
    ..These data suggest that the homologous C1r and C1s genes have remained closely linked after duplication of a common ancestor. The C1r and C1s loci also provide useful polymorphic DNA markers for the short arm of chromosome 12. ..
  37. 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. ..
  38. Gaboriaud C, Gupta R, Martin L, Lacroix M, Serre L, Teillet F, et al. The serine protease domain of MASP-3: enzymatic properties and crystal structure in complex with ecotin. PLoS ONE. 2013;8:e67962 pubmed publisher
  39. 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. ..
  40. Zuraw B, Christiansen S. Pathogenesis and laboratory diagnosis of hereditary angioedema. Allergy Asthma Proc. 2009;30:487-92 pubmed publisher
    ..The knowledge gained concerning the underlying mechanisms of the different types of HAE allow the clinician to approach the laboratory diagnosis with confidence and provides opportunities for novel therapeutic strategies. ..
  41. Garnier G, Circolo A, Xu Y, Volanakis J. Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system. Biochem J. 2003;371:631-40 pubmed
  42. Pelloux S, Thielens N, Hudry Clergeon G, Petillot Y, Filhol O, Arlaud G. Identification of a cryptic protein kinase CK2 phosphorylation site in human complement protease Clr, and its use to probe intramolecular interaction. FEBS Lett. 1996;386:15-20 pubmed
    ..Taken together, these data provide support for the occurrence of a (Ca2+)-dependent interaction between the alpha region and the remainder of the C1r molecule. ..
  43. Duncan R, Wijeyewickrema L, Pike R. The initiating proteases of the complement system: controlling the cleavage. Biochimie. 2008;90:387-95 pubmed
    ..The C1r, C1s and MASP-2 proteases have the most defined roles in the activation of the system. This review focuses on the mechanisms whereby their interaction with substrates and inhibitors is regulated. ..
  44. 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. ..
  45. Arlaud G, Gaboriaud C, Garnier G, Circolo A, Thielens N, Budayova Spano M, et al. Structure, function and molecular genetics of human and murine C1r. Immunobiology. 2002;205:365-82 pubmed
    ..The second part of this review will focus on recent discoveries dealing with a truncated, C1r-related protein, and the occurrence in the mouse of two isoforms, C1rA and C1rB, exhibiting tissue-specific expression patterns. ..
  46. 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
  47. Teillet F, Gaboriaud C, Lacroix M, Martin L, Arlaud G, Thielens N. Crystal structure of the CUB1-EGF-CUB2 domain of human MASP-1/3 and identification of its interaction sites with mannan-binding lectin and ficolins. J Biol Chem. 2008;283:25715-24 pubmed publisher
    ..Based on these and other data, a schematic model of a MBL.MASP complex is proposed. ..
  48. Major B, Kardos J, Kékesi K, Lorincz Z, Zavodszky P, Gal P. Calcium-dependent conformational flexibility of a CUB domain controls activation of the complement serine protease C1r. J Biol Chem. 2010;285:11863-9 pubmed publisher
    ..The physical nature of the behavior of this domain is similar to that of intrinsically unstructured proteins, providing a further example of functionally relevant ligand-induced reorganization of a polypeptide chain. ..
  49. 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. ..
  50. Byun S, Bahk Y, Ryoo Z, Kim K, Hwang H, Lee J, et al. Identification of cDNA encoding a serine protease homologous to human complement C1r precursor from grafted mouse skin. J Invest Dermatol. 2001;116:374-9 pubmed
    ..One of these showed significant sequence homology with human complement C1r precursor. The other clones displayed no homology to any known sequences, however...
  51. Rossi V, Bally I, Lacroix M, Arlaud G, Thielens N. Classical complement pathway components C1r and C1s: purification from human serum and in recombinant form and functional characterization. Methods Mol Biol. 2014;1100:43-60 pubmed publisher
    ..The production of recombinant C1s and of the proenzyme tetramer in a baculovirus-insect cell system, and their purification by affinity chromatography is also presented. ..
  52. Wang T, Secombes C. Complete sequencing and expression of three complement components, C1r, C4 and C1 inhibitor, of the classical activation pathway of the complement system in rainbow trout Oncorhynchus mykiss. Immunogenetics. 2003;55:615-28 pubmed publisher
    ..Low-level constitutive expression of the three components was also detectable in a trout monocyte/macrophage cell line RTS-11, but only the expression of C4 could be upregulated by LPS...
  53. Busby T, Ingham K. NH2-terminal calcium-binding domain of human complement C1s- mediates the interaction of C1r- with C1q. Biochemistry. 1990;29:4613-8 pubmed
    ..These results directly prove that the Ca2(+)-binding sites of C1s as well as all of the determinants necessary for binding of C1s- to C1r- and C1q are located in the NH2-terminal 27-kDa alpha region of the A chain. ..