Affinage

C1S

Complement C1s subcomponent · UniProt P09871

Length
688 aa
Mass
76.7 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C1S encodes a modular serine protease that serves as the catalytic effector of the classical complement pathway, circulating as a zymogen within the Ca2+-dependent C1s-C1r-C1r-C1s tetramer associated with C1q (PMID:23922389, PMID:29311313). C1s is built from an N-terminal interaction region (two EGF-like and two CCP modules plus CUB domains) and a C-terminal trypsin-like serine protease domain (PMID:3500856), and its CUB1-EGF and CUB1-EGF-CUB2 interfaces drive Ca2+-dependent self-association and preferential C1r-C1s heterodimer formation that organizes the compact ring-shaped C1 complex and presents six C1q-binding sites, one per C1q collagen stem (PMID:12788922, PMID:29311313, PMID:19473974). The protease's interaction sites for C1q and C1r reside entirely on the A chain, structurally independent of the catalytic B chain (PMID:2847785). Within C1, surface-bound C1q triggers C1r autoactivation, which cleaves C1s to generate the two-chain active enzyme (PMID:869924); activation repositions zymogen SP-domain loops that otherwise sterically block C4 binding (PMID:23592783). Active C1s then propagates the cascade by cleaving C4 and C2 (generating C2a and C2b, the latter bearing the C4b-binding site) to assemble the C3 convertase (PMID:869924, PMID:70787). Efficient C4 recognition depends on cooperating exosites — the CCP1-CCP2 junction and four positively charged SP-domain residues that engage sulfotyrosine residues on C4 — whereas C2 cleavage is governed by the SP domain alone (PMID:23592783, PMID:9422791, PMID:22855709, PMID:16227207), and intrinsic active-site specificity favors Arg/Lys at P1 (PMID:16169853). C1s activity is controlled by C1 inhibitor (SERPING1), which forms a stable 1:1 covalent SDS-resistant complex with the C1s light chain following second-order kinetics that heparin and polyanions accelerate; the resulting complexes are cleared via LRP (PMID:123251, PMID:3091067, PMID:9388254, PMID:19522701). Beyond complement, C1s cleaves non-canonical substrates including IGFBP-5, beta2-microglobulin, the alarmin HMGB1, and the zymogen of MMP-9, linking the protease to growth-factor signaling, inflammation, and matrix degradation (PMID:10982804, PMID:2110898, PMID:27648302, PMID:8082118). Gain-of-function C1S mutations associated with periodontal Ehlers-Danlos syndrome cause CCP1 misfolding that exposes a cryptic cleavage site, yielding a truncated, unregulated SP fragment (Fg40) with retained esterolytic and HMGB1-cleaving activity but impaired C4 activation that escapes control within the C1 complex (PMID:31921203).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1977 High

    Established that C1s is a two-chain trypsin-like serine protease with narrow specificity that is generated by C1r cleavage and acts on the complement substrates C4 and C2, defining its core enzymatic identity and cascade position.

    Evidence SDS-PAGE, N-terminal sequencing, and esterolytic/cleavage assays on purified C1s, plus C2 fragment characterization by electrophoresis and C4b-Sepharose binding

    PMID:70787 PMID:869924

    Open questions at the time
    • Domain organization and structural basis of specificity not yet resolved
    • Mechanism of activation within the assembled C1 complex not addressed
  2. 1975 High

    Identified C1 inhibitor as the physiological regulator of C1s, forming a stable conformation-dependent 1:1 covalent complex via the C1s light chain — the founding observation of complement protease control.

    Evidence SDS-PAGE, size-exclusion chromatography, and activity assays with acid-denaturation controls

    PMID:123251

    Open questions at the time
    • Kinetics and rate of inhibition not quantified
    • In vivo fate of the inhibited complex unknown
  3. 1987 High

    Determined the complete primary sequence and modular domain architecture of C1s (EGF, CCP, and SP domains), providing the framework for mapping interaction versus catalytic functions.

    Evidence cDNA cloning and nucleotide sequencing from a human liver library with amino acid sequence validation

    PMID:3500856

    Open questions at the time
    • Functional contribution of individual domains not yet dissected
    • Three-dimensional structure unresolved
  4. 1988 High

    Localized all C1q- and C1r-binding capacity to the A chain and showed the catalytic B chain is structurally independent, separating assembly functions from proteolysis; also mapped the C1r/C1s gene pair to chromosome 12p13 with liver-predominant expression.

    Evidence Limited proteolysis, exclusion chromatography, hemolytic reconstitution; genomic Southern/RNA blot and in situ hybridization

    PMID:2459702 PMID:2847785

    Open questions at the time
    • Atomic details of the interaction interfaces not yet defined
    • Regulation of tissue-specific expression not addressed
  5. 1992 High

    Quantified Ca2+-dependent C1s self-association and showed that catalytic post-translational modifications (beta-hydroxylation, sialylation, one N-glycan) are dispensable for C1 assembly and activation, clarifying which features are essential for function.

    Evidence Sedimentation equilibrium ultracentrifugation; baculovirus expression with site-directed mutagenesis and hemolytic assays

    PMID:1445906 PMID:1533159

    Open questions at the time
    • Structural basis of the high-affinity interfacial Ca2+ site not resolved
    • Role of glycans in stability/secretion not examined
  6. 1998 High

    Demonstrated that both CCP modules are required for efficient C4 cleavage (~70-fold loss without CCP1) while C2 cleavage is CCP-independent, establishing that the CCP modules carry C4-specific substrate-recognition exosites.

    Evidence Baculovirus expression of truncated recombinant C1s with quantitative cleavage assays

    PMID:9422791

    Open questions at the time
    • Molecular nature of the CCP exosite contacts not defined
    • Generalizability to other substrates untested
  7. 2003 High

    Solved the CUB1-EGF structure showing a Ca2+-stabilized head-to-tail homodimer and a novel Ca2+-binding CUB module, providing the structural basis for Ca2+-dependent C1r-C1s association and C1q binding.

    Evidence X-ray crystallography at 1.5 Å with Ca2+ coordination analysis

    PMID:12788922

    Open questions at the time
    • Heterodimer (vs homodimer) interface not yet captured
    • Arrangement within the intact tetramer unresolved
  8. 2005 High

    Mapped active-site specificity (P1 Arg/Lys dominant) and used C1s/MASP-2 chimeras to localize C4-cleavage efficiency to the CCP modules and C2-cleavage efficiency to the SP domain, partitioning substrate selectivity across the molecule.

    Evidence Randomized phage display library with kinetics; baculovirus chimeric proteins with kinetic cleavage assays and C1 reconstitution

    PMID:16169853 PMID:16227207

    Open questions at the time
    • Atomic contacts of the CCP-mediated C4 exosite not yet visualized
    • Determinants of non-complement substrate selection not addressed
  9. 2012 High

    Identified four positively charged SP-domain residues forming a catalytic exosite that engages sulfotyrosines on C4, providing the molecular basis for high-efficiency C4 recognition beyond the active site.

    Evidence Site-directed mutagenesis, crystallographic sulfate coordination, and peptide binding assays

    PMID:22855709

    Open questions at the time
    • Coordination of SP exosite with CCP exosite during catalysis not fully integrated
    • Contribution to C2 cleavage not defined
  10. 2013 High

    Defined the structural logic of zymogen-to-active transition and the architecture of C1: zymogen SP loops sterically block C4 binding until activation, and C1q stems contact CUB-module lysines/acidic residues to organize the compact head-to-tail tetramer poised for activation.

    Evidence X-ray crystallography of zymogen CCP1-CCP2-SP and of C1s–collagen/tetramer complexes, with SPR and mutagenesis validation

    PMID:23592783 PMID:23922389

    Open questions at the time
    • Dynamic conformational steps of in-situ activation not directly observed
    • How surface binding mechanically triggers C1r remained partly inferred
  11. 2018 High

    Resolved the C1r-C1s CUB1-EGF-CUB2 heterodimer as an antiparallel L-shaped, Ca2+-bridged assembly with more extensive contacts than homodimers, explaining preferential heterocomplex formation and proposing activation by separation of dimer pairs upon C1q surface binding.

    Evidence X-ray crystallography and biophysical analysis

    PMID:29311313

    Open questions at the time
    • Direct visualization of the activation conformational change in intact C1 not achieved
    • Kinetics of the dimer-separation step not measured
  12. 1997 High

    Established that C1-inhibitor·C1s complexes are catabolized via the LRP receptor, defining the clearance route for spent protease-inhibitor complexes.

    Evidence Cell binding assays, in vivo clearance with RAP inhibition, and LRP-deficient fibroblasts

    PMID:9388254

    Open questions at the time
    • LRP-binding determinants on the complex not mapped
    • Quantitative contribution relative to other clearance routes unknown
  13. 1986 High

    Quantified C1 inhibitor as a covalent second-order inactivator of C1s and showed heparin accelerates inhibition up to 35-fold, defining a tunable regulatory mechanism later extended to other polyanions.

    Evidence Esterolytic kinetics, HPLC size-exclusion, fluorescence probes; later kinetic assays with a polyanion-binding-deficient chimeric serpin

    PMID:19522701 PMID:3091067

    Open questions at the time
    • Physiological polyanion(s) modulating C1s in vivo not identified
    • Biphasic concentration dependence mechanism only partly explained
  14. 1998 Medium

    Showed anti-C1-inhibitor autoantibodies convert C1 inhibitor into a cleavable substrate that fails to form a stable covalent complex, defining an acquired mechanism of dysregulated C1s activity.

    Evidence SDS-PAGE complex analysis, esterolytic assays, and peptide competition mapping

    PMID:9508789

    Open questions at the time
    • Single-lab finding without independent replication
    • In vivo relevance to specific patient phenotypes not established
  15. 2000 High

    Extended C1s function beyond complement by identifying it as the fibroblast protease that selectively cleaves IGFBP-5, linking C1s to growth-factor bioavailability under C1-inhibitor control.

    Evidence Protein purification, sequencing, IGFBP-5 zymography, C4 cleavage and C1-inhibitor inhibition assays

    PMID:10982804

    Open questions at the time
    • Physiological/in vivo significance of IGFBP-5 cleavage not established
    • Selectivity determinants for IGFBP-5 over IGFBP-1–4 not defined
  16. 1990 High

    Identified beta2-microglobulin (cleaved at Lys-58) as the first non-complement protein substrate of C1s, broadening the recognized substrate repertoire.

    Evidence In vitro protease assay with product sequencing and C1 esterase inhibitor control

    PMID:2110898

    Open questions at the time
    • Biological consequence of beta2-microglobulin cleavage not determined
    • In vivo occurrence not demonstrated
  17. 2016 High

    Showed that C1s, both purified and within the C1 complex, cleaves the alarmin HMGB1 into defined fragments that lose pro-inflammatory cytokine-enhancing activity, and identified additional intracellular substrates, implicating C1s in modulating inflammation during apoptotic-cell handling.

    Evidence In vitro protease assays, mass spectrometry, and monocyte/macrophage/DC cytokine production assays

    PMID:27648302

    Open questions at the time
    • In vivo contribution to inflammation resolution not established
    • Functional impact of the additional intracellular substrates not characterized
  18. 2016 High

    Provided the molecular basis of periodontal Ehlers-Danlos syndrome by showing pEDS C1S mutations misfold CCP1, exposing a cryptic cleavage site that yields a truncated, regulation-escaping SP fragment with altered substrate behavior.

    Evidence Cell transfection, recombinant purification, mass spectrometry, N-terminal sequencing, and enzymatic assays on two independent mutants

    PMID:31921203

    Open questions at the time
    • In vivo substrate spectrum and tissue consequences of Fg40 not defined
    • Link between altered proteolysis and connective-tissue pathology mechanistically incomplete
  19. 1994 Medium

    Reported that C1s activates the MMP-9 zymogen, proposing a role in cartilage matrix degradation alongside complement-independent proteolysis.

    Evidence Immunohistochemistry and in vitro zymogen activation assay

    PMID:8082118

    Open questions at the time
    • Single in vitro activation assay with limited functional follow-up
    • In vivo relevance to matrix turnover not demonstrated
  20. 2016 Medium

    Implicated C1s in tumor-cell-autonomous pro-survival signaling, where knockdown reduced ERK/Akt activation, increased apoptosis, and suppressed xenograft tumor growth.

    Evidence shRNA knockdown, Western blot for ERK/Akt, and xenograft assays in cutaneous SCC cells

    PMID:31049937

    Open questions at the time
    • C1r and C1s knocked down together, limiting attribution to C1s alone
    • Molecular link between C1s proteolysis and ERK/Akt signaling undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how C1s's non-complement substrate cleavages (IGFBP-5, beta2-microglobulin, HMGB1, MMP-9) and its tumor pro-survival signaling role operate in vivo, and how substrate selection is governed outside the canonical C4/C2 exosite framework.
  • No in vivo demonstration of physiological non-complement substrate cleavage
  • Signaling mechanism downstream of C1s in tumor cells unmapped
  • Substrate-recognition rules for non-complement targets undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016787 hydrolase activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-168256 Immune System 4
Partners
C1QAC1RC2C4LRP1SERPING1
Complex memberships
C1 complex (C1q-C1r2-C1s2)C1s-C1r-C1r-C1s tetramerC1s–C1 inhibitor (SERPING1) covalent complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1977 Activated C1s (C̄1s) consists of two polypeptide chains of ~56 kDa ('a' chain) and ~27 kDa ('b' chain); the 'b' chain bears the serine protease domain with trypsin-like homology. C1s hydrolyzes lysine ester bonds and cleaves C1s substrate C4 but does not cleave amino acid esters nor protein substrates other than those in the complement cascade, demonstrating its narrow specificity. Activated C1r cleaves C1s to generate the two-chain active form. SDS-PAGE, amino acid sequencing, N-terminal sequence analysis, esterolytic activity assays The Biochemical journal High 869924
1977 C1s cleaves C2 into two antigenically distinct fragments: C2a (73 kDa, larger, more acidic) and C2b (34 kDa, smaller, more basic). C2b contains the C4b-binding site and remains associated with C4b after C2a decay-release from the C3 convertase. In vitro cleavage assay, disc electrophoresis, immunoelectrophoresis, C4b-Sepharose binding assay Proceedings of the National Academy of Sciences of the United States of America High 70787
1975 C1 inhibitor forms a stable 1:1 molar SDS/urea-resistant complex with C1s via the light chain of C1s. Complex formation requires native (non-denatured) C1 inhibitor conformation. Plasmin degrades C1 inhibitor but at least one derivative retains the ability to complex C1s. SDS-PAGE, size-exclusion chromatography, enzyme activity assays, acid denaturation controls The Journal of clinical investigation High 123251
2000 Crystal structure of the C1s catalytic fragment (CCP2 + serine protease domain) resolved to 1.7 Å. The SP domain shows restricted access to subsidiary substrate binding sites, explaining narrow specificity. The CCP2 module is oriented perpendicularly to the SP domain surface via a rigid interface involving proline- and tyrosine-rich segments, and CCP2 provides additional substrate recognition sites for C4. X-ray crystallography at 1.7 Å resolution The EMBO journal High 10775260
1987 The complete amino acid sequence of human C1s (673 residues + 15-residue leader) was determined from cDNA. The N-terminal chain (422 residues) contains five domains including two EGF-like repeats, two CCP modules, and domains homologous to C1r. The C-terminal chain (251 residues) is the serine protease domain. cDNA cloning and nucleotide sequencing from human liver library, supported by amino acid sequence data European journal of biochemistry High 3500856
2003 Crystal structure of the C1s CUB1-EGF interaction domain resolved to 1.5 Å reveals a head-to-tail homodimer; Ca2+ is bound to the EGF module stabilizing intra- and inter-monomer interfaces. A second Ca2+ is bound to the CUB1 module via Glu45, Asp53, Asp98, defining a novel Ca2+-binding CUB module subset. This domain mediates Ca2+-dependent C1r-C1s association and C1q interaction. X-ray crystallography at 1.5 Å, Ca2+ coordination analysis The Journal of biological chemistry High 12788922
2013 Crystal structure of a zymogen C1s construct (CCP1-CCP2-SP) reveals that two loops (492–499 and 573–580) in the zymogen SP domain adopt a conformation that sterically abrogates C4 binding. Activation repositions these loops to interact with sulfotyrosine residues on C4. SPR confirmed that only active C1s (not zymogen) binds C4. The CCP1-CCP2 junction constitutes an exosite for C4 recognition. X-ray crystallography, surface plasmon resonance (SPR) The Journal of biological chemistry High 23592783
2013 C1q collagen-like stems bind C1s (and C1r) via a Ca2+-dependent mechanism involving a lysine side chain (critical residues LysB61 and LysC58 of C1q contacting acidic Ca2+-coordinating residues in C1r/C1s CUB modules). In C1, C1s forms a compact ring-shaped tetramer with a unique head-to-tail interaction at its center, enabling activation by C1r and access to substrates C4 and C2. X-ray crystallography (C1s–collagen peptide complex; C1s tetramer), SPR mutagenesis validation Proceedings of the National Academy of Sciences of the United States of America High 23922389
2018 Crystal structure of the C1r-C1s CUB1-EGF-CUB2 heterodimer reveals an antiparallel L-shaped arrangement with Ca2+ at the interface from each subcomponent. Contacts involve all three domains of each protease and are more extensive than homodimers, explaining preferential heterocomplex formation. In C1, two C1r-C1s dimers are linked via the C1r catalytic domains; activation is driven by separation of the dimer pairs upon C1q surface binding. X-ray crystallography, biophysical analysis Proceedings of the National Academy of Sciences of the United States of America High 29311313
1998 Both CCP modules of C1s are required for efficient C4 cleavage: deletion of CCP1 reduces C4-cleaving activity ~70-fold and deletion of both CCP modules abolishes it. C2 cleavage is minimally affected by CCP deletion. The carbohydrate moiety on CCP2 has no significant effect on catalytic activity. Baculovirus expression of truncated recombinant C1s fragments, functional cleavage assays The Journal of biological chemistry High 9422791
2005 Phage display randomized library profiling revealed that C1s substrate specificity is determined primarily by the P1 position (Arg/Lys), followed by P3 (Leu/Val preferred) and P2 (Gly/Ala preferred), with the S2' position preferring Leu. Prime subsites collectively contribute to cleavage efficiency. Randomized phage display library, kinetic substrate assays The Journal of biological chemistry High 16169853
2012 Four positively charged residues on the C1s SP domain form a catalytic exosite required for efficient C4 cleavage; these residues coordinate a sulfate ion in the crystal structure. C1s interacts with a peptide from C4 containing three sulfotyrosine residues via this exosite. Site-directed mutagenesis, crystal structure analysis, peptide binding assays Journal of immunology High 22855709
2009 C1r CUB1 and CUB2 modules provide high-affinity C1q-binding sites, and C1s CUB1 provides lower-affinity sites; all sites involve acidic residues that also contribute Ca2+ ligands. Together the C1s-C1r-C1r-C1s tetramer contributes six C1q-binding sites, one per C1q stem. A previous model invoking ionic bonds from the C1r EGF Glu137-Glu-Asp139 stretch was ruled out by mutagenesis. Site-directed mutagenesis of C1r/C1s, SPR binding assays The Journal of biological chemistry High 19473974
2000 C1s is the serine protease secreted by human fibroblasts that cleaves insulin-like growth factor-binding protein-5 (IGFBP-5) but not IGFBP-1 through -4. C1r undergoes autoactivation in fibroblast medium and the activated form cleaves C1s; the activated C1s cleaves both C4 and IGFBP-5. C1 inhibitor inhibits this IGFBP-5 cleavage. Protein purification, immunoaffinity chromatography, amino acid sequencing, IGFBP-5 zymography, C4 cleavage assay, C1 inhibitor inhibition assay The Journal of biological chemistry High 10982804
1990 Activated C1s cleaves beta2-microglobulin at Lys-58, generating a two-chain modified form; this is the first demonstrated non-complement protein substrate for C1s. Cleavage is inhibited by C1 esterase inhibitor. In vitro protease assay, mass spectrometry (sequence analysis of cleavage products), C1 esterase inhibitor inhibition European journal of biochemistry High 2110898
2016 C1s (both purified and as part of the C1 complex) cleaves the nuclear alarmin HMGB1 into defined 19 kDa and 12 kDa fragments, diminishing HMGB1's ability to enhance LPS-mediated pro-inflammatory cytokine production from monocytes, macrophages and dendritic cells. Mass spectrometry of C1 complex-treated apoptotic cell proteins identified additional intracellular C1s substrates. In vitro protease assay with purified C1s and C1 complex, SDS-PAGE, mass spectrometry, cytokine production assay Cell death discovery High 27648302
1992 C1s undergoes Ca2+-dependent self-association to form a dimer. The monomer has a single Ca2+-binding site (K ~3×10^5 M^-1); the dimer has three Ca2+-binding sites, with one high-affinity interfacial site (K ~1×10^8 M^-1) driving dimerization. Sedimentation equilibrium ultracentrifugation over wide concentration ranges Biochemistry High 1445906
1986 C1s inhibition by C1 inhibitor follows pure second-order kinetics with a bimolecular rate constant of 6.0×10^4 M^-1 s^-1 at 30°C, forming a covalent complex. Heparin accelerates the rate up to 35-fold and binds all three components (enzyme, inhibitor, complex) with similar affinity (Kd 2.0–3.3 μM). Continuous esterolytic activity monitoring, HPLC size-exclusion chromatography, fluorescence probes Biochemistry High 3091067
1988 The B chain (serine protease domain) of C1s is structurally and functionally independent of the A chain interaction domain. A C1s derivative lacking most of the B chain (C1s-A) retains the ability to dimerize, form C1r2s2 tetramers, and associate with C1q, but is catalytically inactive. All C1q- and C1r-binding sites of C1s are located on the A chain. Trypsin-limited proteolysis, fast exclusion chromatography, thermal denaturation fluorimetry, functional reconstitution hemolytic assay Biochemistry High 2847785
1997 C1-inhibitor–C1s complexes are cleared in vivo via the low density lipoprotein receptor-related protein (LRP). Cellular degradation of C1-INH·C1s is inhibited by chloroquine and by receptor-associated protein (RAP, an LRP inhibitor); LRP-deficient fibroblasts do not degrade the complex. C1-INH·C1s does not stimulate neutrophil or monocyte chemotaxis. Cell binding assays (HepG2, neutrophils, monocytes), in vivo clearance with RAP inhibition, LRP-knockout fibroblasts The Journal of biological chemistry High 9388254
1994 C1s activates the zymogen of matrix metalloproteinase 9 (MMP-9), suggesting coordinated participation of C1s and MMP-9 in cartilage matrix degradation. Immunohistochemistry, in vitro zymogen activation assay Cell and tissue research Medium 8082118
2005 Chimeric C1s/MASP-2 molecules show that higher C4 cleavage efficiency of MASP-2 arises from the CCP modules (nanomolar vs micromolar Km with C4). C2 cleavage efficiency is determined by the SP domain. C1s CCP modules are not required for C1r binding, C1q association, or tetramer assembly. Baculovirus expression of chimeric proteins, kinetic substrate cleavage assays, C1 complex reconstitution The Journal of biological chemistry High 16227207
1992 Recombinant C1s lacking beta-hydroxyasparagine at Asn134, sialic acid, and one N-linked carbohydrate chain (Asn159→Gln mutant) still reassembles with C1q and C1r to form functional C1 and initiates the classical complement pathway, demonstrating these post-translational modifications are not critical for C1 assembly or activation. Baculovirus expression, site-directed mutagenesis, sedimentation analysis, hemolytic assay Biochemistry High 1533159
1987 On cardiolipin (CL) vesicles, C1s can be activated independently of C1r: a C1q-dependent, Ca2+-sensitive binding of dimeric C1s to CL vesicles occurs, and bound C1s is specifically cleaved at 37°C into active 58 kDa and 28 kDa chains in the absence of C1r. Anti-CL antibodies inhibit this C1q-mediated C1s cleavage. Immunochemical analysis, SDS-PAGE, complement activation assays with C1 component depletion Journal of immunology Medium 3029222
1999 Active C1s (detected by activation-specific antibody M241) is present in degenerating cartilage of rheumatoid arthritis but not osteoarthritis. TNF-alpha increases C1s production by chondrocytes in vitro. Activated C1s in cartilage is proposed to participate in pathogenesis through collagenolytic activity. Immunohistochemistry with activation-state-specific monoclonal antibody, ELISA for cytokine regulation Annals of the rheumatic diseases Medium 10364916
1983 C1s is synthesized and secreted by resting human monocytes; stimulation by lymphokine-conditioned media increases C1s secretion and also induces C1r and C1 inhibitor secretion. The whole C1 complex can potentially be assembled locally. Metabolic labeling, immunoprecipitation, SDS-PAGE, functional complement assays from monocyte cultures The Biochemical journal Medium 6318736
1998 Anti-C1-inhibitor autoantibodies prevent formation of stable covalent C1s–C1 inhibitor complexes by converting C1 inhibitor to a substrate: C1s cleaves C1 inhibitor but a stable covalent bond does not form. Peptides 2 (aa 438–449) and 3 (aa 448–459) of C1 inhibitor block autoantibody activity and restore C1s inhibition. SDS-PAGE complex analysis, esterolytic activity assays, peptide competition assays Molecular medicine Medium 9508789
2009 Polyanions (dextran sulfate, heparin) bind C1s directly and exert a biphasic effect on its proteolytic activity (enhancement at low, inhibition at high concentrations). Polyanion-mediated acceleration of C1s–SERPING1 (C1 inhibitor) interaction requires both protease-polyanion and serpin-polyanion interactions. Kinetic inhibition assays, chimaeric alpha1-antitrypsin mutant unable to bind polyanions The Biochemical journal Medium 19522701
1986 Intradermal injection of C1s in guinea pigs causes increased vascular permeability; this effect requires complement component C2, as C2-deficient guinea pigs fail to show permeability increase. C2-deficient animals respond normally to bradykinin and kallikrein. Reconstitution with guinea pig C2 restores C1s-induced permeability. In vivo intradermal injection, genetic complement-deficient animals, component reconstitution Journal of immunology Medium 3487577
2016 Knockdown of C1s (and C1r) in cutaneous squamous cell carcinoma cells inhibited ERK1/2 and Akt activation, promoted apoptosis, and suppressed tumor growth and vascularization in xenograft models, demonstrating a tumor-cell-autonomous pro-survival signaling role for C1s. shRNA knockdown, Western blot for ERK/Akt, xenograft tumor growth assay The British journal of dermatology Medium 31049937
2016 Two pEDS-associated C1S missense mutations (p.Val316del and p.Cys294Arg) cause local CCP1 module misfolding, exposing a cryptic cleavage site (Lys353-Cys354). Cells expressing mutant C1s secrete only a truncated Fg40 fragment (40 kDa) containing the intact SP domain but lacking the N-terminal interaction domains. Fg40 retains esterolytic activity and HMGB1-cleaving activity but has impaired C4 activation; it escapes physiological control within the C1 complex. Cell transfection, recombinant protein purification, mass spectrometry, N-terminal sequencing, enzymatic activity assays Frontiers in immunology High 31921203
2019 C1s (hamster/CHO-derived) is responsible for proteolysis of recombinant HIV gp120 in CHO cells at a specific serine-protease-sensitive epitope. CRISPR/Cas9 knockout of C1s in CHO cells eliminates this proteolytic clipping activity. CRISPR/Cas9 gene knockout, recombinant protein expression, Western blot analysis Biotechnology and bioengineering Medium 31087560
1988 The human C1r and C1s genes are located in a tail-to-tail arrangement on chromosome 12p13, approximately 9.5 kb apart. Both genes are primarily expressed in liver; C1s mRNA undergoes alternative polyadenylation generating multiple transcript sizes. Southern blot, genomic DNA sequencing, RNA blot analysis, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America High 2459702

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. The Journal of experimental medicine 509 1460414
1975 Studies on human plasma C1 inactivator-enzyme interactions. I. Mechanisms of interaction with C1s, plasmin, and trypsin. The Journal of clinical investigation 228 123251
1977 The structure and enzymic activities of the C1r and C1s subcomponents of C1, the first component of human serum complement. The Biochemical journal 141 869924
1983 Biosynthesis in vitro of complement subcomponents C1q, C1s and C1 inhibitor by resting and stimulated human monocytes. The Biochemical journal 130 6318736
1977 Cleavage of C2 by C1s into the antigenically distinct fragments C2a and C2b: demonstration of binding of C2b to C4b. Proceedings of the National Academy of Sciences of the United States of America 124 70787
2014 TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood 122 24695853
1989 Formation of C1s-C1-inhibitor, kallikrein-C1-inhibitor, and plasmin-alpha 2-plasmin-inhibitor complexes during cardiopulmonary bypass. Blood 118 2917186
2000 Crystal structure of the catalytic domain of human complement c1s: a serine protease with a handle. The EMBO journal 92 10775260
2000 Interaction of C1q and mannan-binding lectin (MBL) with C1r, C1s, MBL-associated serine proteases 1 and 2, and the MBL-associated protein MAp19. Journal of immunology (Baltimore, Md. : 1950) 89 10878362
1987 Molecular cloning of cDNA for human complement component C1s. The complete amino acid sequence. European journal of biochemistry 87 3500856
1996 Improvements on the purification of mannan-binding lectin and demonstration of its Ca(2+)-independent association with a C1s-like serine protease. The Biochemical journal 83 8912663
2013 Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation. Proceedings of the National Academy of Sciences of the United States of America 80 23922389
2016 Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement. American journal of human genetics 79 27745832
1993 Inhibition of plasmin, urokinase, tissue plasminogen activator, and C1S by a myxoma virus serine proteinase inhibitor. The Journal of biological chemistry 76 8416956
2019 Tumour-cell-derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma. The British journal of dermatology 73 31049937
2017 Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection-results from a first-in-patient phase 1 trial. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 73 28980446
2003 X-ray structure of the Ca2+-binding interaction domain of C1s. Insights into the assembly of the C1 complex of complement. The Journal of biological chemistry 70 12788922
2000 The complement component C1s is the protease that accounts for cleavage of insulin-like growth factor-binding protein-5 in fibroblast medium. The Journal of biological chemistry 70 10982804
2009 Identification of the C1q-binding Sites of Human C1r and C1s: a refined three-dimensional model of the C1 complex of complement. The Journal of biological chemistry 66 19473974
2004 Structural and functional characterization of complement C4 and C1s-like molecules in teleost fish: insights into the evolution of classical and alternative pathways. Journal of immunology (Baltimore, Md. : 1950) 65 15210793
2001 Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits. Journal of immunology (Baltimore, Md. : 1950) 63 11673555
2004 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. Journal of molecular biology 62 15364579
1988 Human genes for complement components C1r and C1s in a close tail-to-tail arrangement. Proceedings of the National Academy of Sciences of the United States of America 60 2459702
2018 Structure of the C1r-C1s interaction of the C1 complex of complement activation. Proceedings of the National Academy of Sciences of the United States of America 58 29311313
1998 Baculovirus-mediated expression of truncated modular fragments from the catalytic region of human complement serine protease C1s. Evidence for the involvement of both complement control protein modules in the recognition of the C4 protein substrate. The Journal of biological chemistry 58 9422791
2009 Early complement proteases: C1r, C1s and MASPs. A structural insight into activation and functions. Molecular immunology 56 19477526
1993 A new member of the C1s family of complement proteins found in a bactericidal factor, Ra-reactive factor, in human serum. Biochemical and biophysical research communications 53 8240317
2013 Expression of recombinant human complement C1q allows identification of the C1r/C1s-binding sites. Proceedings of the National Academy of Sciences of the United States of America 51 23650384
1999 Complement C1s activation in degenerating articular cartilage of rheumatoid arthritis patients: immunohistochemical studies with an active form specific antibody. Annals of the rheumatic diseases 48 10364916
1990 Limited proteolysis of beta 2-microglobulin at Lys-58 by complement component C1s. European journal of biochemistry 48 2110898
1991 Complement components C1r/C1s, bone morphogenic protein 1 and Xenopus laevis developmentally regulated protein UVS.2 share common repeats. FEBS letters 45 2026272
2001 Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases. Journal of immunology (Baltimore, Md. : 1950) 44 11390518
1997 A neoepitope-based enzyme immunoassay for quantification of C1-inhibitor in complex with C1r and C1s. Scandinavian journal of immunology 44 9420617
1986 Kinetics of interaction of C1 inhibitor with complement C1s. Biochemistry 44 3091067
1994 Immunolocalization of complement C1s and matrix metalloproteinase 9 (92kDa gelatinase/type IV collagenase) in the primary ossification center of the human femur. Cell and tissue research 43 8082118
1989 Complement genes C1r and C1s feature an intronless serine protease domain closely related to haptoglobin. Journal of molecular biology 41 2553984
1979 Staphylococcus aureus opsonization mediated via the classical and alternative complement pathways. A kinetic study using MgEGTA chelated serum and human sera deficient in IgG and complement factors C1s and C2. Immunology 40 108204
1994 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. Journal of immunology (Baltimore, Md. : 1950) 39 8133044
2009 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. Molecular & cellular proteomics : MCP 37 20008834
2007 Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene. Molecular immunology 37 18062908
1997 C1 inhibitor-C1s complexes are internalized and degraded by the low density lipoprotein receptor-related protein. The Journal of biological chemistry 37 9388254
1995 Structure of the catalytic region of human complement protease C1s: study by chemical cross-linking and three-dimensional homology modeling. Biochemistry 37 7779774
2005 Elucidation of the substrate specificity of the C1s protease of the classical complement pathway. The Journal of biological chemistry 36 16169853
2015 An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 35 25904443
2005 Functional characterization of complement proteases C1s/mannan-binding lectin-associated serine protease-2 (MASP-2) chimeras reveals the higher C4 recognition efficacy of the MASP-2 complement control protein modules. The Journal of biological chemistry 33 16227207
1988 Domain structure, stability, and interactions of human complement C1s-: characterization of a derivative lacking most of the B chain. Biochemistry 32 2847785
1983 C1 inactivator-C1s complexes in inflammatory joint disease. Clinical and experimental immunology 32 6604603
1988 Assignment of the complement serine protease genes C1r and C1s to chromosome 12 region 12p13. Human genetics 30 2834284
2022 Complement C1s as a diagnostic marker and therapeutic target: Progress and propective. Frontiers in immunology 29 36275687
2016 Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity. Clinical immunology (Orlando, Fla.) 29 26769276
1992 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 29 1533159
1995 Complement components C1q, C1r/C1s, and C1INH in rheumatoid arthritis. Correlation of in situ hybridization and northern blot results with function and protein concentration in synovium and primary cell cultures. Arthritis and rheumatism 28 7718002
1987 Antibody-independent activation of C1. I. Differences in the mechanism of C1 activation by nonimmune activators and by immune complexes: C1r-independent activation of C1s by cardiolipin vesicles. Journal of immunology (Baltimore, Md. : 1950) 28 3029222
2022 Distinction of early complement classical and lectin pathway activation via quantification of C1s/C1-INH and MASP-1/C1-INH complexes using novel ELISAs. Frontiers in immunology 27 36420270
2020 Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program. Blood advances 27 32176765
2017 Blockade of HLA Antibody-Triggered Classical Complement Activation in Sera From Subjects Dosed With the Anti-C1s Monoclonal Antibody TNT009-Results from a Randomized First-in-Human Phase 1 Trial. Transplantation 26 28926521
1992 Calcium-linked self-association of human complement C1s. Biochemistry 26 1445906
2013 A molecular switch governs the interaction between the human complement protease C1s and its substrate, complement C4. The Journal of biological chemistry 25 23592783
2012 Identification of a catalytic exosite for complement component C4 on the serine protease domain of C1s. Journal of immunology (Baltimore, Md. : 1950) 25 22855709
2001 Molecular cloning of the complement (C1r/C1s/MASP2-like serine proteases from the common carp (Cyprinus carpio). Immunogenetics 25 11220628
1996 Exon structure of the gene encoding the human mannose-binding protein-associated serine protease light chain: comparison with complement C1r and C1s genes. International immunology 25 8921412
1983 Heparin-stimulated modification of C1-inhibitor by subcomponent C1s of human complement. Hoppe-Seyler's Zeitschrift fur physiologische Chemie 25 6602754
2019 C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmune Human B Cells In Vitro. Journal of immunology (Baltimore, Md. : 1950) 24 30635392
2019 Identification and CRISPR/Cas9 Inactivation of the C1s Protease Responsible for Proteolysis of Recombinant Proteins Produced in CHO Cells. Biotechnology and bioengineering 24 31087560
1986 C1s-induced vascular permeability in C2-deficient guinea pigs. Journal of immunology (Baltimore, Md. : 1950) 24 3487577
1986 Hypocomplementemia with low C1s-C1 inhibitor complex in systemic lupus erythematosus. Arthritis and rheumatism 23 3492208
1985 Characterization of C1q, C1s and C-1 Inh synthesized by stimulated human monocytes in vitro. FEBS letters 23 3876244
1981 Immunofluorescence studies on the subcomponents of the first component of complement (C1): detection of C1q and C1s in different cells of biopsy material and on human as well as on guinea pig peritoneal macrophages. Immunobiology 23 7011949
1986 Biosynthesis of complement C1 inhibitor by Hep G2 cells. Reactivity of different glycosylated forms of the inhibitor with C1s. The Biochemical journal 22 3099750
2023 An innovative phase 2 proof-of-concept trial design to evaluate SAR445088, a monoclonal antibody targeting complement C1s in chronic inflammatory demyelinating polyneuropathy. Journal of the peripheral nervous system : JPNS 21 37119056
2016 Proteolytic inactivation of nuclear alarmin high-mobility group box 1 by complement protease C1s during apoptosis. Cell death discovery 21 27648302
1999 Structure and functions of the interaction domains of C1r and C1s: keystones of the architecture of the C1 complex. Immunopharmacology 21 10408360
1998 Mechanism of action of anti-C1-inhibitor autoantibodies: prevention of the formation of stable C1s-C1-inh complexes. Molecular medicine (Cambridge, Mass.) 21 9508789
1998 Selective complement C1s deficiency caused by homozygous four-base deletion in the C1s gene. Human genetics 21 9856483
1991 Biochemical characterization and tissue distribution of hamster complement C1s. Journal of immunology (Baltimore, Md. : 1950) 21 1898597
1985 Determination of C1s-C1 inhibitor complexes in plasma by means of an enzyme linked immunosorbent assay. Clinical and experimental immunology 21 3874014
1984 Structure and activity of C1r and C1s. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 21 6149574
2017 C1r and C1s from Nile tilapia (Oreochromis niloticus): Molecular characterization, transcriptional profiling upon bacterial and IFN-γ inductions and potential role in response to bacterial infection. Fish & shellfish immunology 20 28882800
1985 Changes in protein conformation and stability accompany complex formation between human C1 inhibitor and C1-s. Biochemistry 20 3874650
2023 Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease. American journal of hematology 19 37246953
2012 Zebrafish scube1 (signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 1) is involved in primitive hematopoiesis. The Journal of biological chemistry 19 23271740
2010 Mapping surface accessibility of the C1r/C1s tetramer by chemical modification and mass spectrometry provides new insights into assembly of the human C1 complex. The Journal of biological chemistry 19 20592021
2024 Safety, tolerability, and activity of the active C1s antibody riliprubart in cold agglutinin disease: a phase 1b study. Blood 18 38085846
2017 Effect of the Anti-C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody-Induced Complement Activation-A Preclinical In Vitro Study. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 18 28251805
2014 Classical complement pathway components C1r and C1s: purification from human serum and in recombinant form and functional characterization. Methods in molecular biology (Clifton, N.J.) 18 24218249
2003 Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system. The Biochemical journal 18 12513694
1992 Selective deficiency of C1s associated with a systemic lupus erythematosus-like syndrome. Report of a case. Arthritis and rheumatism 18 1575792
2002 alpha(1)-Proteinase inhibitor mutants with specificity for plasma kallikrein and C1s but not C1. Protein science : a publication of the Protein Society 17 12192078
1994 Unique C1 inhibitor dysfunction in a kindred without angioedema. I. A mutant C1 INH that inhibits C1-s but not C1-r. Journal of immunology (Baltimore, Md. : 1950) 17 8144914
2002 Functional characterization of human mannose-binding lectin-associated serine protease (MASP)-1/3 and MASP-2 promoters, and comparison with the C1s promoter. International immunology 16 12356684
2015 Characterization of rock bream (Oplegnathus fasciatus) complement components C1r and C1s in terms of molecular aspects, genomic modulation, and immune responsive transcriptional profiles following bacterial and viral pathogen exposure. Fish & shellfish immunology 15 26241508
2002 C1s, the protease messenger of C1. Structure, function and physiological significance. Immunobiology 15 12396001
1997 Expression and characterization of a 159 amino acid, N-terminal fragment of human complement component C1s. Molecular immunology 15 9683269
1996 Change of complement C1s synthesis during development of hamster cartilage. Cell and tissue research 15 8766156
1986 Biosynthesis of the subcomponents C1q, C1r and C1s of the first component of complement (C1) by guinea pig hepatocyte primary cultures. European journal of immunology 15 3019707
2019 Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes. Frontiers in immunology 14 31921203
2004 A novel series of potent and selective small molecule inhibitors of the complement component C1s. Bioorganic & medicinal chemistry letters 14 15149641
1998 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 14 9524231
2009 Modulation of the proteolytic activity of the complement protease C1s by polyanions: implications for polyanion-mediated acceleration of interaction between C1s and SERPING1. The Biochemical journal 13 19522701
1997 Coordinated change between complement C1s production and chondrocyte differentiation in vitro. Cell and tissue research 13 9211832

Missed literature

Know a paper Affinage missed for C1S? Flag it for the maintainers and the community.

No submissions yet.