Affinage

C1S

Complement C1s subcomponent · UniProt P09871

Length
688 aa
Mass
76.7 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C1S encodes a modular serine protease that functions as the catalytic effector of the classical complement C1 complex (C1q·C1r₂·C1s₂), where it is activated by C1r cleavage and then sequentially cleaves complement components C4 and C2 to initiate the classical pathway cascade. The N-terminal CUB1-EGF-CUB2 domains mediate Ca²⁺-dependent homodimerization, heterodimer formation with C1r, and interaction with C1q collagen stems (PMID:12788922, PMID:29311313, PMID:23922389), while the C-terminal CCP1-CCP2-SP region provides substrate recognition: both CCP modules and a sulfotyrosine-interacting exosite on the SP domain are required for efficient C4 cleavage, whereas C2 cleavage depends primarily on the SP domain alone (PMID:9422791, PMID:22855709, PMID:23592783). C1s activity is regulated by C1-INH, which forms a covalent 1:1 complex with the SP domain that is cleared via LRP (PMID:123251, PMID:9388254); beyond complement, C1s cleaves non-complement substrates including IGFBP-5, β₂-microglobulin, HMGB1, and pro-MMP-9 (PMID:10982804, PMID:2110898, PMID:27648302, PMID:8082118). Heterozygous missense mutations in C1S cause periodontal Ehlers-Danlos syndrome (pEDS), producing a truncated ~40 kDa fragment that retains protease activity but escapes C1-complex regulation (PMID:27745832, PMID:31921203).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1975 High

    Establishing how C1s is controlled: demonstration that C1-INH forms a stable 1:1 covalent complex with the C1s light chain (SP domain) resolved the identity and stoichiometry of the primary physiological inhibitor.

    Evidence In vitro reconstitution with purified proteins; SDS-PAGE and size-exclusion chromatography under denaturing conditions

    PMID:123251

    Open questions at the time
    • Mechanism of covalent bond formation not yet resolved at atomic level
    • In vivo half-life of C1s–C1-INH complex not determined
  2. 1977 High

    Defining the activation cascade within C1: showing that C1r activates C1s (but not other substrates) and that activated C1s cleaves C2 into C2a and C2b established the sequential C1r→C1s→C2 proteolytic order and the origin of the C3 convertase.

    Evidence Purified component reconstitution; SDS-PAGE; esterolytic assays; gel electrophoresis and C4b-binding assays

    PMID:70787 PMID:869924

    Open questions at the time
    • Structural basis of C1r recognition of C1s cleavage site unknown
    • Rate constants for C1s cleavage of C2 in the context of C4b not measured
  3. 1988 High

    Functional separation of interaction and catalytic domains: showing that the A chain (N-terminal, non-catalytic) contains all sites for Ca²⁺-dependent dimerization, C1r₂-C1s₂ tetramer formation, and C1q binding, while the B chain (catalytic) is structurally independent, defined C1s as a bipartite molecule.

    Evidence Tryptic fragmentation; size-exclusion chromatography; reconstitution of C1 complex; hemolytic assays

    PMID:2847785

    Open questions at the time
    • Precise domain boundaries for each interaction not mapped at residue level
  4. 1990 High

    Discovery of non-complement substrates: cleavage of β₂-microglobulin at Lys-58 by C1s, blocked by C1-INH, established that C1s has proteolytic activity beyond complement components, later extended to IGFBP-5, HMGB1, and pro-MMP-9.

    Evidence In vitro cleavage with purified C1s; peptide sequencing; inhibitor controls; subsequent studies with conditioned medium, MS, and cytokine assays

    PMID:10982804 PMID:2110898 PMID:27648302 PMID:8082118

    Open questions at the time
    • Physiological significance of most non-complement cleavages in vivo remains undemonstrated
    • Full non-complement substrate repertoire not systematically defined
  5. 1992 High

    Biophysical characterization of Ca²⁺-driven self-association: analytical ultracentrifugation revealed one monomer Ca²⁺ site and a high-affinity interfacial Ca²⁺ site driving dimerization, providing a quantitative thermodynamic framework for C1s assembly.

    Evidence Sedimentation equilibrium ultracentrifugation over a range of protein and Ca²⁺ concentrations with thermodynamic modeling

    PMID:1445906

    Open questions at the time
    • Relationship between homodimer and C1r–C1s heterodimer Ca²⁺ requirements not compared
  6. 1998 High

    Defining domain requirements for substrate discrimination: deletion of CCP modules reduced C4 cleavage ~70-fold while C2 cleavage was minimally affected, establishing that the CCP modules provide an exosite essential for C4 but not C2 recognition.

    Evidence Baculovirus expression of truncated C1s constructs; functional C4 and C2 cleavage assays

    PMID:9422791

    Open questions at the time
    • Exact residues on CCP modules contacting C4 not yet identified
  7. 2000 High

    Atomic-resolution view of the catalytic region: the 1.7 Å crystal structure of C1s CCP2-SP revealed a chymotrypsin-fold SP domain with restricted subsidiary site access (explaining narrow specificity) and a rigid CCP2–SP interface, providing the first structural template for inhibitor/drug design.

    Evidence X-ray crystallography at 1.7 Å resolution

    PMID:10775260

    Open questions at the time
    • No structure of C1s in complex with a macromolecular substrate (C4 or C2)
  8. 2003 High

    Structural basis of Ca²⁺-dependent homodimerization: the 1.5 Å crystal structure of CUB1-EGF revealed a head-to-tail homodimer with Ca²⁺ ions at both EGF and CUB1 modules stabilizing intra- and inter-monomer contacts.

    Evidence X-ray crystallography at 1.5 Å

    PMID:12788922

    Open questions at the time
    • Why the heterodimer with C1r is preferred over the homodimer was not explained
  9. 2005 High

    Extended specificity profiling: phage display identified S3 (Leu/Val), S2 (Gly/Ala), and S2' (Leu) preferences, and CCP-swap chimeras between C1s and MASP-2 showed CCP modules tune C4 Km 21–27-fold without affecting C1 complex assembly.

    Evidence Randomized phage display library; kinetic peptide assays; domain-swap chimeras with baculovirus expression and hemolytic reconstitution

    PMID:16169853 PMID:16227207

    Open questions at the time
    • Structural basis for the CCP-dependent Km difference between C1s and MASP-2 not resolved
  10. 2009 High

    Mapping C1q-binding sites on the tetramer: mutagenesis and SPR demonstrated that C1s CUB1 contributes lower-affinity C1q-binding sites involving acidic Ca²⁺-coordinating residues, complementing higher-affinity sites on C1r CUB1/CUB2.

    Evidence Site-directed mutagenesis of CUB modules; surface plasmon resonance

    PMID:19473974

    Open questions at the time
    • Relative energetic contributions of individual C1q stems to overall avidity not quantified
  11. 2012 High

    Identification of a sulfotyrosine-binding exosite: four positively charged SP domain residues coordinate a sulfate ion in the crystal and interact with a C4 sulfotyrosine peptide; mutagenesis confirmed their requirement for efficient C4 cleavage, revealing a post-translational recognition mechanism.

    Evidence Site-directed mutagenesis; functional C4 cleavage assays; crystallographic sulfate binding; peptide binding

    PMID:22855709

    Open questions at the time
    • Whether sulfotyrosine modification of C4 is regulated and thus rate-limiting in vivo is unknown
  12. 2013 High

    Zymogen-to-active conformational switch for C4 recognition: crystal structure of zymogen C1s CCP1-CCP2-SP showed two loops sterically blocking the C4-binding surface, which reposition upon activation; co-crystal with a collagen peptide showed C1q stem Lys contacts Ca²⁺-coordinating residues on C1s CUB.

    Evidence X-ray crystallography of zymogen and collagen-bound C1s; SPR comparing zymogen vs. active C1s binding to C4

    PMID:23592783 PMID:23650384 PMID:23922389

    Open questions at the time
    • Full-length C1s structure in the context of the intact C1 complex not yet determined
  13. 2016 High

    Genetic link to connective tissue disease: heterozygous C1S missense mutations were identified as causative for periodontal Ehlers-Danlos syndrome across 19 families, with mutant C1s showing intracellular retention and ER enlargement.

    Evidence Whole-exome/targeted sequencing of 19 pEDS families; cell biology of mutant protein

    PMID:27745832

    Open questions at the time
    • Mechanism linking complement protease gain-of-function to connective tissue degradation not defined
    • Effect on C1 complex stoichiometry in patient serum not measured
  14. 2018 High

    Structural explanation for preferential C1r–C1s heterodimerization: the co-crystal of the C1r–C1s CUB1-EGF-CUB2 heterodimer revealed an antiparallel L-shaped arrangement with more extensive Ca²⁺-mediated interfacial contacts than homodimers.

    Evidence X-ray crystallography of C1r/C1s heterodimeric co-crystal

    PMID:29311313

    Open questions at the time
    • Dynamics of heterodimer formation and any role of chaperones in assembly unknown
  15. 2019 High

    pEDS mutations produce an unregulated truncated protease: two different pEDS C1S mutations each caused secretion of a ~40 kDa C-terminal fragment (Fg40) lacking the C1q/C1r-interaction domain; Fg40 retained esterolytic and HMGB1-cleaving activity but lost C4 cleavage, explaining how the mutant escapes C1-complex control.

    Evidence Stable HEK293-F transfection; recombinant protein purification; mass spectrometry; N-terminal sequencing; functional assays

    PMID:31921203

    Open questions at the time
    • Whether Fg40 circulates in pEDS patient serum and its in vivo substrates are unknown
    • Mechanism of aberrant intracellular cleavage generating Fg40 not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural model of C1s in the context of the fully assembled C1 complex, the precise mechanism by which pEDS-associated C1s protease activity causes connective tissue pathology, and the full physiological relevance of non-complement substrates remain to be established.
  • No cryo-EM or crystal structure of intact C1 complex at high resolution showing C1s positioning
  • Causal pathway from unregulated C1s protease to periodontal tissue destruction undefined
  • In vivo significance of C1s cleavage of IGFBP-5, β₂-microglobulin, and MMP-9 not demonstrated

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 4
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-1643685 Disease 2
Partners
C1QAC1RC2C4ALRP1SERPING1
Complex memberships
C1 complex (C1q·C1r₂·C1s₂)C1s–C1-INH covalent complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1977 Activated C1r cleaves C1s (converting it from single-chain zymogen to two-chain active enzyme), and activated C1s cleaves synthetic lysine ester substrates; C1r does not cleave protein substrates other than C1s, establishing the sequential activation order within C1. Biochemical characterization of purified C1r and C1s; SDS-PAGE; amino acid composition; esterolytic assays with synthetic substrates The Biochemical journal High 869924
1977 C1s cleaves C2 into C2a (73 kDa) and C2b (34 kDa); C2b retains binding to C4b while C2a is released, demonstrating C2b contains the stable C4b-binding site after C3 convertase decay. Purified component reconstitution; gel electrophoresis; immunoelectrophoresis; C4b-Sepharose binding assay Proceedings of the National Academy of Sciences of the United States of America High 70787
1975 C1s forms a stable 1:1 molar SDS/urea-resistant complex with C1 inhibitor (C1-INH); the light chain (serine protease domain) of C1s provides the binding site for C1-INH; native conformation of C1-INH is required for complex formation. Purified component incubation; SDS-PAGE; size-exclusion chromatography under denaturing conditions; molar ratio analysis The Journal of clinical investigation High 123251
1986 C1s inhibition by C1-INH follows second-order kinetics (kapp = 6.0 × 10^4 M^-1 s^-1 at 30°C); heparin accelerates inhibition up to 35-fold by binding to all three species (enzyme, inhibitor, complex); Ca2+ has no effect on the rate. Kinetic analysis of esterolytic activity loss; size-exclusion HPLC under dissociating conditions; fluorescence probes Biochemistry High 3091067
2000 Crystal structure of the C1s catalytic fragment (CCP2-SP) at 1.7 Å reveals a chymotrypsin-like serine protease domain with restricted access to subsidiary substrate binding sites (accounting for narrow specificity) and a CCP2 module oriented perpendicularly to the SP domain surface through a rigid proline/tyrosine-rich interface; CCP2 provides additional substrate recognition sites for C4. X-ray crystallography at 1.7 Å resolution The EMBO journal High 10775260
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 CCPs abolishes it, whereas C2 cleavage is affected mainly by the serine protease domain. Baculovirus expression of truncated C1s fragments (CCP2-ap-SP, ap-SP); functional assays for C4 and C2 cleavage; comparison with intact C1s The Journal of biological chemistry High 9422791
2003 Crystal structure of the C1s N-terminal interaction domain (CUB1-EGF) at 1.5 Å reveals a Ca2+-dependent head-to-tail homodimer; one Ca2+ bound to each EGF module stabilizes both intra- and inter-monomer interfaces; a second Ca2+ bound to the CUB1 module; this domain mediates both C1r-C1s association and C1q interaction. X-ray crystallography at 1.5 Å; Ca2+-binding analysis; structural modelling of C1r-C1s heterodimer The Journal of biological chemistry High 12788922
2009 C1q binding to C1s-C1r-C1r-C1s tetramer involves high-affinity sites on C1r CUB1 and CUB2 modules and lower-affinity sites on C1s CUB1; all sites implicate acidic residues that also coordinate Ca2+; six C1q-binding sites total (one per C1q stem) are contributed by the tetramer. Site-directed mutagenesis of C1r and C1s CUB modules; surface plasmon resonance binding assays The Journal of biological chemistry High 19473974
2013 Crystal structure of C1s-collagen peptide complex shows the C1q collagen stem binds a shallow groove on C1s via a critical lysine side chain contacting Ca2+-coordinating residues, explaining Ca2+-dependent C1q/C1s interaction; C1s also forms a compact ring-shaped head-to-tail tetramer in crystal. X-ray crystallography of C1s with synthetic collagen-like peptide; structural analysis of C1s tetramer Proceedings of the National Academy of Sciences of the United States of America High 23922389
2013 C1q residues LysB61 and LysC58 in the collagen-like stem each play a key role in interaction with the C1s-C1r-C1r-C1s tetramer, likely forming salt bridges with outer acidic Ca2+ ligands of C1r and C1s CUB domains. Recombinant C1q expression; site-directed mutagenesis of C1q collagen-stem lysines; surface plasmon resonance Proceedings of the National Academy of Sciences of the United States of America High 23650384
2018 Crystal structure of the CUB1-EGF-CUB2 heterodimer of C1r and C1s at defined resolution reveals an antiparallel L-shaped heterodimer stabilized by Ca2+ from each subunit at the interface; contacts involve all three domains of each protease and are more extensive than homodimers, explaining preferential heterocomplex formation. X-ray crystallography of C1r/C1s CUB1-EGF-CUB2 co-crystal Proceedings of the National Academy of Sciences of the United States of America High 29311313
2013 Transition of C1s from zymogen to active form is essential for C4 binding; crystal structure of zymogen C1s (CCP1-CCP2-SP) reveals loops 492–499 and 573–580 sterically block C4 binding in the zymogen, and repositioning of these loops upon activation permits interaction with sulfotyrosine residues on C4; CCP1-CCP2 junction provides an exosite for C4. Surface plasmon resonance (zymogen vs. active C1s binding to C4); X-ray crystallography of zymogen C1s construct The Journal of biological chemistry High 23592783
2012 Four positively charged residues on the C1s serine protease domain form a catalytic exosite required for efficient C4 cleavage; this exosite coordinates a sulfate ion in crystal structure and interacts with a sulfotyrosine-containing peptide from C4. Site-directed mutagenesis of SP domain residues; functional C4 cleavage assays; crystallographic sulfate-binding observation; peptide binding assay Journal of immunology (Baltimore, Md. : 1950) High 22855709
2005 Full substrate specificity of C1s elucidated: S3 (prefers Leu/Val) and S2 (prefers Gly/Ala) subsites dominate specificity beyond P1 (Arg); S2' prefers Leu; a peptide based on top phage display sequence shows best kinetics of any C1s substrate. Randomized phage display library screening; kinetic peptide substrate assays The Journal of biological chemistry High 16169853
2005 MASP-2 CCP modules confer 21–27-fold higher C4 cleavage efficiency (lower Km) compared to C1s CCP modules; C1s/MASP-2 chimeras with swapped CCP modules retain ability to associate with C1r and C1q in a pseudo-C1 complex and be activated by C1r, demonstrating CCP modules have no direct role in C1r/C1q binding. Multisite-directed mutagenesis to engineer C1s/MASP-2 chimeras; baculovirus expression; C4 and C2 cleavage assays; hemolytic reconstitution assay The Journal of biological chemistry High 16227207
2000 C1s secreted by human fibroblasts cleaves IGFBP-5 but not IGFBP-1 through IGFBP-4; C1r in fibroblast medium undergoes autoactivation and activates C1s; C1-inhibitor blocks IGFBP-5 cleavage, identifying a non-complement substrate of C1s. Purification from conditioned medium; immunoaffinity chromatography; amino acid sequencing; zymography; inhibitor assay The Journal of biological chemistry High 10982804
1990 C1s cleaves beta2-microglobulin at Lys-58 in the disulfide loop, generating a two-chain structure; C1 esterase inhibitor blocks this cleavage; this was the first non-complement protein substrate identified for C1s. In vitro cleavage assay with purified C1s; peptide sequencing; inhibitor assay with C1-INH European journal of biochemistry High 2110898
2016 C1s (as part of C1 complex) proteolytically cleaves HMGB1 into 19 and 12 kDa fragments, diminishing HMGB1's ability to enhance LPS-mediated pro-inflammatory cytokine production from monocytes/macrophages/dendritic cells; mass spectrometry revealed additional intracellular alarmin/autoantigen substrates cleaved by C1s in apoptotic cells. In vitro cleavage assay with purified C1s and C1 complex; mass spectrometry of treated apoptotic cell proteins; cytokine production assay Cell death discovery High 27648302
1994 C1s is inhibited by the poxvirus serpin SERP-1, which forms a stable complex with C1s (association rate constant 1.3 × 10^3 M^-1 s^-1); heparin does not affect this rate. Gel analysis of stable complex formation; kinetic inhibition assays The Journal of biological chemistry Medium 8416956
1992 C1s undergoes Ca2+-dependent self-association to a dimer; the monomer has one Ca2+ binding site (K ~3×10^5 M^-1); the dimer has three Ca2+ binding sites, with one high-affinity interfacial site (K ~10^8 M^-1) driving dimerization. Sedimentation equilibrium ultracentrifugation over a range of protein and Ca2+ concentrations; thermodynamic modeling Biochemistry High 1445906
1988 The A chain (N-terminal, non-catalytic) of C1s contains all sites responsible for Ca2+-dependent dimerization, formation of the C1r2-C1s2 tetramer, and interaction with C1q; the catalytic B chain is structurally and functionally independent. Trypsin digestion of C1s to generate A-chain fragment (C1s-A); fast exclusion chromatography; reconstitution assays for C1r2-C1s2 and C1 complex; hemolytic inhibition assay; thermal stability measurement Biochemistry High 2847785
1992 Recombinant C1s lacking beta-hydroxyasparagine, sialic acid, and one N-linked carbohydrate chain still reassembles with C1q and C1r to form functional C1 complex and activates C4 and C2, demonstrating these post-translational modifications are not critical for C1s function. Baculovirus expression; site-directed mutagenesis (Asn159→Gln); reconstitution of C1 complex; hemolytic activity assay Biochemistry High 1533159
1997 C1-INH complexed with C1s is cleared from circulation via the low-density lipoprotein receptor-related protein (LRP); LRP-deficient fibroblasts fail to degrade C1-INH·C1s complexes; receptor-associated protein (RAP) inhibits in vivo clearance. Binding assays with HepG2 cells; LRP-knockout fibroblasts; RAP inhibition; in vivo clearance studies in mice The Journal of biological chemistry High 9388254
1994 C1s activates the zymogen of MMP-9 (92 kDa gelatinase), co-localizing with MMP-9 in hypertrophic chondrocytes of the primary ossification center, suggesting coordinated roles in cartilage matrix degradation. Immunohistochemistry; MMP-9 zymogen activation assay by C1s Cell and tissue research Medium 8082118
1987 Cardiolipin vesicles can activate C1s bound to C1q independently of C1r (C1r-independent activation of C1s) in a Ca2+-dependent manner; anti-cardiolipin antibodies block this C1q-mediated cleavage of C1s. Purified component reconstitution with phospholipid vesicles; SDS-PAGE analysis of C1s chain cleavage; inhibition with antibody Journal of immunology (Baltimore, Md. : 1950) Medium 3029222
1998 Anti-C1-INH autoantibodies prevent formation of the stable covalent C1s–C1-INH complex (converting C1-INH to a substrate), but do not dissociate preformed complexes; the autoantibody binding site on C1-INH maps to amino acids 448–459. SDS-PAGE of complex formation; esterolytic activity assay; peptide competition assay Molecular medicine (Cambridge, Mass.) Medium 9508789
2009 Polyanions (heparin, dextran sulfate) bind C1s and enhance its proteolytic activity at low concentrations while inhibiting it at higher concentrations; acceleration of C1s–SERPING1 association by polyanions requires interactions with both SERPING1 and C1s. Kinetic inhibition assays; chimaeric alpha1-antitrypsin/SERPING1 mutant; polyanion binding and activity measurements The Biochemical journal Medium 19522701
2016 Heterozygous missense mutations in C1S (at subunit interfaces or inter-domain hinges) cause periodontal Ehlers-Danlos syndrome; mutant C1s is intracellularly retained with mild ER enlargement, linking gain-of-function complement protease variants to connective tissue pathology. Genetic sequencing of 19 pEDS families; identification of C1S and C1R mutations; cell biology (intracellular retention, ER morphology) American journal of human genetics High 27745832
2019 Two different pEDS-associated C1S missense mutations (p.Val316del, p.Cys294Arg) both cause secretion of only a truncated ~40 kDa fragment (Fg40) lacking the N-terminal C1q/C1r-interaction domain; Fg40 retains esterolytic activity and HMGB1 cleavage but cannot cleave C4, escaping normal physiological control within the C1 complex. Stable HEK293-F cell transfection; recombinant protein purification; mass spectrometry; N-terminal sequencing; esterolytic and C4 cleavage assays Frontiers in immunology High 31921203
2010 Mass spectrometry-based chemical modification of lysines shows that upon C1 complex assembly, both C1s CUB1-EGF-CUB2 interaction domains (distant in free tetramer) associate with each other; the C1s serine protease domain is partly positioned inside the C1q cone in the proenzyme C1. Chemical modification with NHS-acetate; LC-MS/MS comparison of isolated tetramer vs. C1 complex; semi-quantitative label-free analysis of 51/73 lysines The Journal of biological chemistry High 20592021
1983 Human monocytes synthesize and secrete C1q and C1s; activation by lymphokines from stimulated lymphocyte cultures additionally induces C1r and C1-INH secretion; liver is also a primary site of C1s synthesis. Pulse-chase metabolic labeling; immunoprecipitation; SDS-PAGE; functional activity assays in primary monocyte cultures The Biochemical journal Medium 6318736
2019 C1s knockdown in cutaneous squamous cell carcinoma (cSCC) cells inhibits ERK1/2 and Akt activation, promotes apoptosis, and suppresses xenograft tumor growth and vascularization, defining a tumor-cell-autonomous growth-promoting role for C1s. siRNA knockdown; Western blotting for pERK1/2 and pAkt; apoptosis assay; xenograft mouse model The British journal of dermatology Medium 31049937
2005 A novel C1r-like protease (C1r-LP) specifically cleaves pro-C1s into two fragments of identical size to the active C1s chains, providing a C1r-independent means of C1s activation; C1r-LP activity is inhibited by C1-INH. Recombinant protein expression; protease activity assay against pro-C1s; SDS-PAGE; C1-INH inhibition assay The Biochemical journal Medium 15527420

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 121 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 78 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
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 72 28980446
2019 Tumour-cell-derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma. The British journal of dermatology 71 31049937
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
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 69 12788922
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) 64 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
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
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 56 29311313
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 50 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
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