Affinage

C9

Complement component C9 · UniProt P02748

Length
559 aa
Mass
63.2 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Complement C9 is the terminal pore-forming component of the membrane attack complex (MAC), responsible for osmotic lysis of target cells and bacteria (PMID:7365242, PMID:34752492). Sequence and topology analysis established that C9 is organized into an N-terminal cysteine-rich half and a C-terminal half that engages lipid and inserts into membranes (PMID:4018030); upon complement activation C9 inserts as an integral membrane protein, behaving as a trypsin-resistant, salt-non-elutable embedded species (PMID:559700) that penetrates fully across the bilayer into the cytoplasmic space (PMID:2857173). Membrane insertion is coupled to a hydrophilic-to-amphiphilic conformational transition: C9 monomers self-associate into close molecular proximity (PMID:6432039) and polymerize into hollow tubular structures of 12–16 subunits forming a transmembrane channel of ~90–100 Å inner diameter (PMID:4055801, PMID:1696352), with insertion and polymerization being mechanistically separable events (PMID:2475785). C9 forms a distinct, larger pore than the C8-initiated lesion, creating a qualitatively new channel that releases large molecules (PMID:7365242), and the circular MAC ring is incidental to lysis rather than obligatory (PMID:3885222). The principal C9-binding site resides within the MACPF domain of C8 alpha, which simultaneously and independently binds C8 beta, C8 gamma, and C9 (PMID:16618117). C9 activity is regulated by an array of extracellular and intracellular factors that act on the activation-dependent conformer: the complement inhibitor CD59 binds the C9b fragment via a 365–371 loop (PMID:1377690, PMID:16844690), clusterin binds C9b and inhibits polymerization (PMID:8345200), S-protein/vitronectin blocks poly-C9 tubule formation within SC5b-9 (PMID:6587746), apolipoproteins A-I/A-II bind polymerized C9 and inhibit assembly (PMID:8429039), and mortalin/GRP75 binds C9 through its ATPase domain to inhibit polymerization and confer resistance to complement-dependent cytotoxicity (PMID:24719326); ecto-CK2-mediated serine phosphorylation of the C9a region reduces hemolytic activity (PMID:10408378, PMID:15902683). Polymerization is essential for efficient bacterial killing, damaging both bacterial membranes, and is blocked by locking the first transmembrane helix or by LPS O-antigen (PMID:34752492). Loss-of-function premature-stop mutations in exons 2 and 4 cause complete complement C9 deficiency (PMID:9144525), and the rare P167S variant increases spontaneous polymerization and lowers plasma C9 levels in association with age-related macular degeneration risk (PMID:33783477, PMID:29767720).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1977 High

    Established that C9 is not merely a peripheral serum protein but physically inserts into the lipid bilayer of the target membrane upon complement activation, defining its identity as an integral membrane protein.

    Evidence Radiolabeled C9 on complement-bearing erythrocytes assayed by proteolytic stripping, salt elution, and SDS extraction

    PMID:559700

    Open questions at the time
    • Did not define which protein segment inserts
    • No structural model of the inserted form
  2. 1980 High

    Distinguished the C9-dependent lesion from the C8 lesion, showing C9 creates a qualitatively larger pore permeable to hemoglobin, explaining why C9 is required for efficient lysis.

    Evidence Dual 86Rb/hemoglobin release assay from sensitized erythrocytes with C8/C9 titration

    PMID:7365242

    Open questions at the time
    • Pore dimensions not yet quantified
    • Mechanism of pore enlargement unclear
  3. 1984 Medium

    Provided early biophysical and structural evidence that C9 polymerization brings monomers into close proximity and that S-protein/vitronectin regulates this assembly within the soluble complex.

    Evidence FITC self-energy-transfer fluorescence during polymerization; reconstitution plus EM and immunogold of SC5b-9

    PMID:6432039 PMID:6587746

    Open questions at the time
    • Geometry of monomer-monomer contacts not resolved
    • S-protein binding site on C9 not mapped
  4. 1985 High

    Defined C9 domain topology and the architecture of the poly-C9 tubule, linking the cysteine-rich N-terminal half and the lipid-inserting C-terminal half to a hollow cylindrical pore.

    Evidence cDNA sequencing with photoaffinity and antibody mapping; transmission and immunoelectron microscopy of poly-C9 with C9a/C9b fragment antibodies

    PMID:3885222 PMID:4018030 PMID:4055801

    Open questions at the time
    • Atomic-resolution structure not determined
    • Mechanism of monomer addition during polymerization unresolved
  5. 1988 High

    Linked C9 to the broader family of pore-forming immune effectors by demonstrating perforin shares sequence homology, establishing an evolutionary and functional connection of membrane-disrupting proteins.

    Evidence N-terminal protein sequencing and cDNA cloning of perforin with alignment to C9

    PMID:3261391

    Open questions at the time
    • Homology described but shared mechanistic motif not yet structurally defined
  6. 1989 High

    Showed that membrane insertion and polymerization of C9 are mechanistically independent steps, refining the model of MAC assembly into separable conformational events.

    Evidence Sequence-specific anti-peptide antibodies capturing refolding conformers with differential inhibition of hemolysis versus polymerization

    PMID:2475785

    Open questions at the time
    • Order and trigger of the two events not fully defined
    • Conformer structures not resolved
  7. 1990 Medium

    Quantified the poly-C9 channel size and showed functional pore diameter scales with C9 content, and demonstrated transmembrane penetration of C9 into the cytoplasmic space.

    Evidence Liposome swelling/molecular sieving with antibody inhibition; intracellular transglutaminase cross-linking of radiolabeled C9

    PMID:1696352 PMID:2857173

    Open questions at the time
    • Stoichiometry of channels in vivo unclear
    • Relationship between sieving radius and physiological pore disputed elsewhere
  8. 1991 Medium

    Provided thermodynamic evidence that C9 is conformationally metastable and partially unfolds at membrane surfaces, offering a physical basis for the insertion-competent transition.

    Evidence Differential scanning calorimetry with ion, pH, EDTA, and choline manipulation

    PMID:2054360

    Open questions at the time
    • In vivo relevance of unfolding transitions inferred, not directly observed
    • No structural intermediate captured
  9. 1993 High

    Identified the activation-dependent conformer of C9 as the target of multiple extracellular inhibitors (clusterin, apolipoproteins A-I/A-II), establishing that the hydrophilic-to-amphiphilic transition exposes regulatory binding sites.

    Evidence Ligand blotting and competition with polymerized C9; saturable binding to polyC9 and inhibition of Zn2+ polymerization and endothelial C5b-9 incorporation

    PMID:8345200 PMID:8429039

    Open questions at the time
    • Precise C9 epitopes for apolipoproteins not mapped
    • Physiological contribution of each inhibitor not quantified
  10. 1997 Medium

    Connected C9 directly to human disease by identifying premature-stop mutations causing complete C9 deficiency, validating C9 loss-of-function genetics.

    Evidence Exon-specific PCR, direct sequencing, and family segregation analysis of C9-deficient patients

    PMID:9144525

    Open questions at the time
    • Clinical phenotype range not addressed here
    • Functional consequence assumed from stop codons rather than protein assays
  11. 1999 Medium

    Revealed post-translational control of C9 activity through ecto-protein kinase phosphorylation of the C9a region that dampens hemolytic function.

    Evidence 32P-phosphorylation by K562 ecto-PK with thrombin fragment mapping, hemolysis assay, and inhibitor panel

    PMID:10408378

    Open questions at the time
    • Phosphorylation stoichiometry low (~3%)
    • Identity of the kinase inferred from inhibitors, not direct
  12. 2005 Medium

    Identified the C9-phosphorylating kinase as ecto-CK2 and showed it protects cancer cells from complement, with elevated activity on tumor cells, suggesting a therapeutic target.

    Evidence CK2-selective pharmacological inhibitors with complement lysis assays and cancer-versus-normal cell comparison

    PMID:15902683

    Open questions at the time
    • CK2 identity inferred from inhibitor selectivity without knockdown
    • Direct C9 phospho-site not mapped in this study
  13. 2006 Medium

    Localized the principal C9-binding site to the C8 alpha MACPF domain and mapped the CD59 recognition loop on C9, defining the molecular contacts that organize MAC assembly and its restriction.

    Evidence Recombinant alphaMACPF complex reconstitution with hemolysis; peptide mapping, binding assays, and docking for the CD59-binding 365–371 loop

    PMID:16618117 PMID:16844690

    Open questions at the time
    • No mutagenesis of C9 itself for the CD59 site
    • Structural model of the C8alpha-C9 interface not solved
  14. 2014 High

    Uncovered an intracellular regulator, mortalin/GRP75, that binds C9 via its ATPase domain and confers complement resistance, expanding C9 regulation beyond the extracellular space.

    Evidence Co-IP, recombinant domain pulldowns, Zn2+-polymerization inhibition, and CDC assays with mortalin overexpression/knockdown/truncation

    PMID:24719326

    Open questions at the time
    • How mitochondrial-targeted mortalin acts on surface C9 not fully resolved
    • Physiological versus protective context unclear
  15. 2021 High

    Established polymerization as the decisive step for efficient bactericidal MAC function and linked the rare P167S variant's enhanced polymerization to AMD risk through a mechanistic gain of function and lowered plasma C9.

    Evidence TMH1-locked polymerization-deficient C9 with bacterial killing/membrane permeability and O-antigen complementation; recombinant P167S/variant polymerization, hemolysis, EM, and patient plasma C9 measurements in independent cohorts

    PMID:29767720 PMID:33783477 PMID:34752492

    Open questions at the time
    • Mechanism by which enhanced polymerization drives AMD pathology in vivo not defined
    • How LPS O-antigen blocks TMH1 engagement not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • An atomic-resolution structure of membrane-inserted poly-C9 and the dynamic pathway from monomer through the conformational transition to the assembled pore remain undefined.
  • No high-resolution structure of the inserted/polymerized state
  • Trigger and sequence of conformational transition not resolved at atomic detail
  • In vivo balance among the many C9 regulators unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2
Pathway
R-HSA-168256 Immune System 3
Partners
APOA1C8AC8BC8GCD59CLUHSPA9VTN
Complex memberships
membrane attack complex (C5b-9 / poly-C9)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 Human C9 cDNA sequencing revealed the protein's topology: the amino-terminal half is cysteine-rich with homology to LDL receptor cysteine-rich domains, and the carboxy-terminal half reacts with lipid-soluble photoaffinity probes consistent with membrane insertion. Monoclonal antibody epitopes were mapped to specific proteolytic fragments, establishing surface topological features of the protein. cDNA sequencing, proteolytic fragmentation, monoclonal antibody epitope mapping on Western blots, photoaffinity probing The EMBO journal High 4018030
1977 C9 (and C8) polypeptide chains insert into the erythrocyte lipid bilayer upon complement activation: cell-bound C9 was resistant to proteolytic stripping and salt elution but recoverable with SDS, and a membrane-embedded 18 kDa trypsin-resistant fragment (~1/4 of native C9) was identified, demonstrating C9 behaves as an integral membrane protein after binding. 125I-radiolabeling of C9 on EAC1-9 erythrocytes, trypsin/chymotrypsin stripping, EDTA elution, SDS extraction, SDS-PAGE Journal of immunology High 559700
1984 S-protein (vitronectin) inhibits C9 polymerization within the SC5b-9 complex: it blocks the membrane site of C5b-7 and prevents poly-C9 tubule formation by SC5b-8, yielding a wedge-shaped non-tubular SC5b-9 complex visualized by electron microscopy; S-protein was localized to the wide end of the wedge-like structure by biotin-avidin-gold labeling. Purified protein reconstitution, SDS-PAGE gradient gels to quantify poly-C9, electron microscopy, immunogold localization with biotinyl-S-protein Acta pathologica, microbiologica, et immunologica Scandinavica. Supplement High 6587746
1985 Electron microscopy of native C9 showed an ellipsoid monomer (70×50 Å) that polymerizes into hollow tubular structures of 12–16 monomers (150 Å outer, 90 Å inner diameter) rimmed by a torus. Immunoelectron microscopy with anti-C9a and anti-C9b antibodies mapped the C9a region to the torus, base, and midsection of poly(C9), while C9b epitopes concentrated at the torus and base, indicating C9a and C9b segments are not segregated in the polymer and that oligosaccharides are peripheral. Transmission electron microscopy, alpha-thrombin cleavage to produce C9a/C9b fragments, immunoelectron microscopy, concanavalin A-gold labeling The Journal of biological chemistry High 4055801
1985 Thrombin-cleaved C9 (C9n, two-chain form) retains full hemolytic activity and can form SDS-resistant poly(C9) rings/strings, but cannot form tubular poly(C9). Classical circular complement lesions seen on erythrocyte ghosts require tubular poly(C9) from intact C9. This showed that the circular membrane lesion is incidental to lysis, not obligatory, and that pore enlargement is not linked to circular MAC formation. Thrombin cleavage of C9, reconstitution of C9-depleted serum, hemolysis assay under single-hit conditions, sucrose/inulin release assay, electron microscopy of ghost membranes Proceedings of the National Academy of Sciences of the United States of America High 3885222
1989 Sequence-specific anti-peptide antibodies captured distinct C9 refolding conformers during membrane insertion, demonstrating that C9 undergoes partial unfolding as it enters the membrane. Some antibodies inhibited C9-mediated haemolysis but not C9 polymerization, while others had the opposite effect, establishing that membrane insertion and polymerization are mechanistically independent processes. Sequence-specific anti-peptide antibodies, haemolysis assay, C9 polymerization assay Nature High 2475785
1988 Perforin (a cytolytic T-cell granule protein) shares primary sequence homology with C9 at functionally conserved regions, providing molecular evidence that perforin is evolutionarily linked to C9 and both perform membrane-disrupting functions. N-terminal amino acid sequencing of purified perforin, cDNA cloning and deduced protein sequence alignment with C9 Nature High 3261391
1992 CD59 binds specifically to the C9b (37 kDa carboxy-terminal) fragment of alpha-thrombin-cleaved C9 and to the C8 alpha chain (not C8 beta or C8 gamma), with half-maximal binding at 35 nM for C9b. Binding requires a conformational change that accompanies surface adsorption and is protein–protein in nature (not phospholipid-mediated). CD59 does not bind native soluble C9 in solution or human C9/C8 from rabbit serum. 125I-CD59 binding assay to plastic/nitrocellulose-adsorbed proteins, density gradient analysis, ligand blotting after thrombin cleavage of C9 and SDS separation of C8 subunits The Journal of biological chemistry High 1377690
1993 Clusterin binds specifically to complement C7, C8 beta, and the C9b fragment of C9 (containing the hydrophobic membrane interaction segment), as shown by ligand blotting. Binding of clusterin to C9 is competed by polymerized C9 but not by monomeric C9 or other complement proteins, indicating that the conformational change during C9's hydrophilic-to-amphiphilic transition exposes the clusterin-binding site. Both clusterin subunits interact with C9 and inhibit C5b-9-mediated hemolysis and Zn2+-induced C9 polymerization. 125I-clusterin ligand blotting in the presence of Tween, competition with polymerized C9, hemolysis inhibition assay, Zn2+-induced polymerization inhibition assay Journal of immunology High 8345200
1993 Apolipoproteins A-I and A-II bind specifically to polymerized C9 (polyC9) but not to monomeric C9, revealing an activation-dependent binding site. ApoA-I and ApoA-II inhibit Zn2+-catalyzed C9 polymerization (complete inhibition at ≥5 µM) and reduce C9 incorporation into C5b-9 complexes on endothelial cells, explaining the protective effect of HDL for cells exposed to complement. Saturable binding assay to polyC9 vs. monomeric C9, Zn2+-induced polymerization assay, C9 incorporation into C5b-9 on endothelial cells by flow cytometry/gel analysis The Journal of biological chemistry High 8429039
1980 C9 produces a distinct membrane lesion mechanistically different from the C8-initiated lesion: C9 generates a separate pore capable of large-molecule (hemoglobin) release, while C8 alone creates a smaller pore permeable to 86Rb but not hemoglobin. Addition of C9 at concentrations insufficient to alone cause 86Rb release nevertheless produced substantial 86Rb release, establishing that C9 acts by creating a qualitatively new membrane channel. 86Rb and hemoglobin dual-release assay from sensitized erythrocytes, kinetic analysis, titration of C8 and C9 concentrations Journal of immunology High 7365242
1990 C9 and C8 penetrate across the erythrocyte membrane into the cytoplasmic space during C5b-9 assembly: intracellular transglutaminase cross-linked radiolabeled C9 and C8 to high molecular weight species, demonstrating transmembrane penetration. The experiment controlled for enzyme leakage by adding dimethylcasein extracellularly. Intracellular transglutaminase cross-linking of 125I-C8 and 125I-C9 in erythrocyte ghosts, SDS-PAGE under reducing conditions The Journal of biological chemistry High 2857173
2006 A 6-residue sequence (residues 365–371) within a 25-residue disulfide-bonded loop of C9 was identified as the primary CD59 recognition domain. Peptide binding, functional hemolysis assays, and computational docking showed that both C8 alpha and C9 bind to a similar or overlapping hydrophobic pocket on CD59. Peptide screens, peptide binding assays, functional complement lysis assays, computer modeling and docking The Journal of biological chemistry Medium 16844690
1999 C9 is phosphorylated on serine residue(s) in the N-terminal C9a portion by an ecto-protein kinase on the surface of K562 leukemia cells. Phosphorylated C9 (stoichiometry ~3%) shows reduced hemolytic activity. Polymerized C9 and reduced/alkylated C9 are not and are, respectively, substrates for this ecto-PK. Heparin and 2,3-diphosphoglycerate prevented phosphorylation, suggesting the ecto-PK is related to CK2. 32P-phosphorylation assay with K562 ecto-PK, thrombin cleavage mapping to C9a fragment, hemolysis assay, inhibitor panel Immunopharmacology Medium 10408378
2005 Ecto-protein kinase CK2 on the surface of Raji B lymphoma cells phosphorylates complement C9, protecting cells from complement-mediated lysis. CK2 inhibitors (TBB, Emodin, DRB) enhanced killing by Rituximab and human complement, and extracellular CK2 inhibition enhanced C8/C9-mediated lysis of C5b-7-bearing cells. Ecto-CK2 activity is higher on cancer cells than on normal fibroblasts and blood cells. CK2-selective pharmacological inhibitors, complement lysis assay, anti-CD59 antibody blockade, comparison of cancer vs. normal cell ecto-PK activity European journal of immunology Medium 15902683
2006 The MACPF domain of C8 alpha simultaneously binds C8 beta, C8 gamma, and C9, forming a noncovalent alphaMACPF·C8 beta·C8 gamma·C9 complex. A recombinant alphaMACPF-gamma dimer also bound C8 beta and C9 and was hemolytically active, establishing that the principal C9-binding site lies within the MACPF domain of C8 alpha and that binding sites for C8 beta, C8 gamma, and C9 are distinct. Recombinant expression of alphaMACPF and alphaMACPF-gamma in E. coli, noncovalent complex formation, hemolysis assay Biochemistry High 16618117
1991 Differential scanning calorimetry of C9 revealed three endothermic unfolding transitions (Tm ~32, 48, 53°C) and an exothermic aggregation transition. Calcium ions stabilize the protein (shifting Tm1 from 32 to 35.8°C), chaotropic agents and EDTA lower transition temperatures, and choline (present on membrane surfaces) lowers transitions close to body temperature. This suggested C9 is partially unfolded at membrane surfaces in vivo, facilitating membrane insertion. High-sensitivity differential scanning calorimetry with ion and pH variation, EDTA chelation, thrombin proteolysis Biochemistry Medium 2054360
1990 Poly C9 channels have an estimated pore radius of ~45–50 Å (diameter 90–100 Å) as determined by molecular sieving. As C9 is added in increasing C8:C9 ratios (1:1 to 1:12) during C5b-9 assembly, functional channel size increases. Monoclonal antibodies to C9 neoantigen (poly-C9) inhibit C5b-9 channels, while anti-C8 antibodies inhibit C5b-8 channels. Liposome swelling assay, Renkin equation analysis, molecular sieving with iodinated protein markers, monoclonal antibody inhibition Molecular immunology Medium 1696352
1984 FITC-labeled C9 undergoes a 40–60% decrease in fluorescence emission and increased anisotropy upon activation and polymerization by C5b-8 membranes, due to self-energy transfer between closely apposed fluorescein chromophores in polymerized C9. This established that C9 polymerization brings individual C9 monomers into close molecular proximity. Fluorescein isothiocyanate labeling of C9, fluorescence emission, steady-state anisotropy, fluorescence lifetime measurements during C5b-8-induced polymerization and heat polymerization Biochemistry Medium 6432039
1987 C9 is required for the production of leukotriene B4 (LTB4) and prostaglandins from rat polymorphonuclear leukocytes (PMNs) stimulated by complement: LTB4 release was strictly dependent on C9 being present in the C5b-9 complex. Extracellular calcium was also required; in its absence LTB4 release was completely abolished and arachidonic acid release was markedly reduced. Complement reconstitution assay on [3H]arachidonic acid-labeled PMNs with defined complement complexes (C5b-7, C5b-8, C5b-9), calcium chelation (EGTA), kinetic measurement of labeled LTB4 and prostanoid release Molecular immunology Medium 2828929
2014 Mortalin/GRP75 (mitochondrial HSP70) binds complement C9 (and C8) via its N-terminal ATPase domain through ionic, nucleotide-sensitive interactions, and inhibits Zn2+-induced C9 polymerization. Overexpression of mortalin reduces C5b-9 deposition on cells and provides resistance to complement-dependent cytotoxicity (CDC), while mortalin knockdown enhances CDC sensitivity. Mitochondrial targeting of mortalin is required for its full protective effect. Co-immunoprecipitation, recombinant ATPase and substrate-binding domain pulldown assays, Zn2+-induced C9 polymerization inhibition assay, complement lysis assay with mortalin overexpression/knockdown/truncation constructs, C5b-9 quantification by flow cytometry The Journal of biological chemistry High 24719326
2013 Hepatitis C virus (HCV) core protein suppresses C9 mRNA and protein expression in hepatocytes. Promoter analysis identified the TCF-4E transcription factor as responsible for HCV core-mediated C9 promoter regulation. Sera from chronically HCV-infected patients showed reduced C5b-9 levels and a reduced antimicrobial effect on model organisms, demonstrating functional impairment of MAC. RT-PCR and protein expression analysis of HCV-infected hepatocytes and liver biopsies, C9 promoter-reporter assay, TCF-4E functional analysis, hemolytic/antimicrobial assay of patient sera Journal of virology Medium 23487461
1997 The human C9 gene is composed of 11 exons on chromosome 5p13. Two point mutations causing premature stop codons were identified in C9-deficient patients: a C→A exchange at cDNA position 166 in exon 2, and a C→T exchange at cDNA position 464 in exon 4, both generating TGA stop codons. Family studies showed these mutations segregate independently, explaining the complete C9 deficiency in the probands. Exon-specific PCR, direct DNA sequencing, exon-intron boundary sequencing, family segregation analysis Journal of immunology Medium 9144525
2021 C9 polymerization strongly enhances damage to both the outer and inner bacterial membrane and accelerates killing of E. coli and Klebsiella in serum. Locking the first transmembrane helix domain (TMH1) of C9 prevents its polymerization without affecting binding to C5b-8. An excess of C9 is required for efficient polymeric C9 formation on bacteria. LPS O-antigen in complement-resistant E. coli specifically impairs C9 polymerization; restoring O-antigen expression caused complement resistance by blocking polymerization. Site-directed mutagenesis to lock C9 TMH1, flow cytometry for C9 binding, inner/outer membrane permeability assays, serum killing assay, O-antigen complementation in E. coli PLoS pathogens High 34752492
2021 The rare C9 P167S AMD risk variant displays increased spontaneous polymerization and a small increase in hemolytic activity compared to wild-type C9. Electron microscopy showed identical MAC ring structures for P167S and wild-type C9. Patients carrying P167S have significantly lower C9 plasma levels, suggesting enhanced polymerization-driven clearance. The variant's increased polymerization provides a mechanistic basis for its AMD risk association. Recombinant production of WT and P167S C9, electron microscopy of MAC structures, polymerization assay, hemolysis of sheep erythrocytes in C9-depleted serum, plasma C9 level measurement in two independent patient cohorts Human molecular genetics High 33783477
2018 Five novel rare C9 variants (p.M45L, p.F62S, p.G126R, p.T170I, p.A529T) were identified in AMD patients. In vitro analysis showed p.P167S spontaneously aggregates while p.F62S and other variants fail to polymerize in the presence of zinc. The p.F62S and p.P167S mutants showed decreased hemolysis of erythrocytes and RPE-19 cells by carrier sera. The data demonstrate that these AMD-associated C9 variants affect secretion and polymerization without influencing classical lytic activity. Recombinant expression of C9 variants, Zn2+-induced polymerization assay, hemolysis assay with C9-depleted serum reconstituted with variants, measurement of serum C9 levels and sC5b-9 in carriers vs. non-carriers Human molecular genetics Medium 29767720
1988 The exon-intron structure of the human C9 gene shows correlation between splice sites and surface features of the protein, but little correlation with putative protein domain structure. Notably, despite the LDL receptor cysteine-rich domain being present in both C9 and the LDL receptor, the intron boundaries do not coincide at the same positions, suggesting that substantial exon-intron rearrangement occurred before or after domain exchange, challenging simple exon-shuffling models. Genomic C9 gene sequencing, exon-intron boundary analysis, comparison with LDL receptor gene structure Biochemistry Medium 3219351
1993 Trout C9 contains an additional C-terminal thrombospondin domain absent from human C9. Despite this, alternative pathway complement activation generates circular MAC lesions on erythrocyte membranes, demonstrating that the thrombospondin domain does not restrict C9 polymerization. Trout C9 does not bind to human C7 or C8 (no lysis of erythrocytes bearing human C5b-7 or C5b-8 after addition of trout serum containing EDTA), indicating species-specific binding interactions. Re-sequencing of 3' trout C9 cDNA, alternative pathway activation on rabbit erythrocytes, electron microscopy of MAC lesions, cross-species complement reconstitution assay Developmental and comparative immunology Medium 8449252

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nature genetics 293 24036952
1988 Homology of perforin to the ninth component of complement (C9). Nature 266 3261391
2013 Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma. Cell death & disease 204 23579273
1985 The sequence and topology of human complement component C9. The EMBO journal 177 4018030
1993 Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9. Journal of immunology (Baltimore, Md. : 1950) 140 8345200
1989 Cloning, analysis, and expression of murine perforin 1 cDNA, a component of cytolytic T-cell granules with homology to complement component C9. Proceedings of the National Academy of Sciences of the United States of America 127 2783486
1984 Inhibition of C9 polymerization within the SC5b-9 complex of complement by S-protein. Acta pathologica, microbiologica, et immunologica Scandinavica. Supplement 108 6587746
1992 The human complement regulatory protein CD59 binds to the alpha-chain of C8 and to the "b"domain of C9. The Journal of biological chemistry 105 1377690
2005 Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids. Biochemistry 98 15865448
1977 On the mechanism of cell membrane damage by complement: evidence on insertion of polypeptide chains from C8 and C9 into the lipid bilayer of erythrocytes. Journal of immunology (Baltimore, Md. : 1950) 95 559700
1996 Phosphorylation of C8 and C9 subunits of the multicatalytic proteinase by casein kinase II and identification of the C8 phosphorylation sites by direct mutagenesis. Biochemistry 85 8619999
2016 Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: Completing the picture. Neurology(R) neuroimmunology & neuroinflammation 84 27844039
2006 Defining the CD59-C9 binding interaction. The Journal of biological chemistry 84 16844690
2019 Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model. Neuron 80 31831332
1995 Structure of the human C7 gene and comparison with the C6, C8A, C8B, and C9 genes. Journal of immunology (Baltimore, Md. : 1950) 80 7730625
1993 Interaction between apolipoproteins A-I and A-II and the membrane attack complex of complement. Affinity of the apoproteins for polymeric C9. The Journal of biological chemistry 80 8429039
2002 Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: roles of protein kinase Cdelta, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation. Molecular pharmacology 78 11809859
1996 Complement in acute and chronic arthritides: assessment of C3c, C9, and protectin (CD59) in synovial membrane. Annals of the rheumatic diseases 76 9014582
1987 Complementary DNA cloning of complement C8 beta and its sequence homology to C9. Biochemistry 71 3651397
1985 Proteolytic modification of human complement protein C9: loss of poly(C9) and circular lesion formation without impairment of function. Proceedings of the National Academy of Sciences of the United States of America 65 3885222
2020 C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD? Acta neuropathologica 59 32876811
2020 TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS. eLife 59 33300868
2009 Candida albicans sphingolipid C9-methyltransferase is involved in hyphal elongation. Microbiology (Reading, England) 59 20019081
2005 Identification of fungal sphingolipid C9-methyltransferases by phylogenetic profiling. The Journal of biological chemistry 57 16339149
2010 Upregulation of plasma C9 protein in gastric cancer patients. Proteomics 55 20707004
1976 Acute phase proteins and C9 in patients with Behcet's syndrome and aphthous ulcers. Clinical and experimental immunology 54 1086750
2017 Unraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS. Frontiers in neuroscience 52 29326544
2011 Trichinella spiralis paramyosin binds to C8 and C9 and protects the tissue-dwelling nematode from being attacked by host complement. PLoS neglected tropical diseases 51 21750743
2006 Activation of complement C3, C5, and C9 genes in tumors treated by photodynamic therapy. Cancer immunology, immunotherapy : CII 49 16947020
2002 Attenuation of experimental allergic encephalomyelitis in complement component 6-deficient rats is associated with reduced complement C9 deposition, P-selectin expression, and cellular infiltrate in spinal cords. Journal of immunology (Baltimore, Md. : 1950) 49 11970970
2000 Deregulated expression of homeobox-containing genes, HOXB6, B8, C8, C9, and Cdx-1, in human colon cancer cell lines. Biochemical and biophysical research communications 48 10833444
2003 Design, synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists. Journal of medicinal chemistry 47 12646033
2002 Similar effects of c9,t11-CLA and t10,c12-CLA on immune cell functions in mice. Lipids 46 12216844
2006 Biosynthesis of C9-aldehydes in the moss Physcomitrella patens. Biochimica et biophysica acta 45 16630744
2019 C9-ALS/FTD-linked proline-arginine dipeptide repeat protein associates with paraspeckle components and increases paraspeckle formation. Cell death & disease 43 31582731
2020 Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD. Cell reports 42 32755582
1988 Relationships between the gene and protein structure in human complement component C9. Biochemistry 42 3219351
2014 c9,t11-Conjugated linoleic acid ameliorates steatosis by modulating mitochondrial uncoupling and Nrf2 pathway. Journal of lipid research 41 24634500
2012 C9-R95X polymorphism in patients with neovascular age-related macular degeneration. Investigative ophthalmology & visual science 41 22190594
2016 The NEU1-selective sialidase inhibitor, C9-butyl-amide-DANA, blocks sialidase activity and NEU1-mediated bioactivities in human lung in vitro and murine lung in vivo. Glycobiology 40 27226251
2013 Hepatitis C virus suppresses C9 complement synthesis and impairs membrane attack complex function. Journal of virology 40 23487461
2009 Thauera butanivorans sp. nov., a C2-C9 alkane-oxidizing bacterium previously referred to as 'Pseudomonas butanovora'. International journal of systematic and evolutionary microbiology 40 19528200
2007 Probes for narcotic receptor mediated phenomena. 34. Synthesis and structure-activity relationships of a potent mu-agonist delta-antagonist and an exceedingly potent antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethylmorphan series. Journal of medicinal chemistry 40 17625813
2015 Homeobox C9 suppresses Beclin1-mediated autophagy in glioblastoma by directly inhibiting the transcription of death-associated protein kinase 1. Neuro-oncology 39 26582930
1993 Domain structure, functional activity, and polymerization of trout complement protein C9. Developmental and comparative immunology 37 8449252
1989 Detection of refolding conformers of complement protein C9 during insertion into membranes. Nature 37 2475785
2020 Survival and Motor Phenotypes in FVB C9-500 ALS/FTD BAC Transgenic Mice Reproduced by Multiple Labs. Neuron 36 33022226
1997 Cloning and sequencing of complement component C9 and its linkage to DOC-2 in the pufferfish Fugu rubripes. Gene 36 9373156
1985 The architecture of complement component C9 and poly(C9). The Journal of biological chemistry 36 4055801
2016 Functional characterization of the Aspergillus nidulans glucosylceramide pathway reveals that LCB Δ8-desaturation and C9-methylation are relevant to filamentous growth, lipid raft localization and Psd1 defensin activity. Molecular microbiology 35 27479571
1998 Expression of complement C4 and C9 genes by human astrocytes. Brain research 35 9795119
1990 Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10. Similarities to and differences from C9. The Journal of experimental medicine 35 2303785
2018 Vaccinia Virus C9 Ankyrin Repeat/F-Box Protein Is a Newly Identified Antagonist of the Type I Interferon-Induced Antiviral State. Journal of virology 34 29444943
2014 Mortalin/GRP75 binds to complement C9 and plays a role in resistance to complement-dependent cytotoxicity. The Journal of biological chemistry 34 24719326
2003 Vaccenic acid (t11-18:1) is converted to c9,t11-CLA in MCF-7 and SW480 cancer cells. Lipids 33 12934672
1986 Human alveolar macrophages synthesize the functional alternative pathway of complement and active C5 and C9 in vitro. Scandinavian journal of immunology 33 3787189
1980 Distinction between C8-mediated and C8/C9-mediated hemolysis on the basis of independent 86Rb and hemoglobin release. Journal of immunology (Baltimore, Md. : 1950) 33 7365242
2010 The utility of C4d, C9, and troponin T immunohistochemistry in acute myocardial infarction. Archives of pathology & laboratory medicine 32 20121615
2005 Extracellular phosphorylation of C9 by protein kinase CK2 regulates complement-mediated lysis. European journal of immunology 32 15902683
1984 Complement protein C9 labeled with fluorescein isothiocyanate can be used to monitor C9 polymerization and formation of the cytolytic membrane lesion. Biochemistry 32 6432039
2009 Anti-angiogenic and vascular disrupting effects of C9, a new microtubule-depolymerizing agent. British journal of pharmacology 30 19302593
1991 Thermal unfolding and aggregation of human complement protein C9: a differential scanning calorimetry study. Biochemistry 30 2054360
2018 The proline-arginine repeat protein linked to C9-ALS/FTD causes neuronal toxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis. Cell death & disease 29 30250194
2014 Chemerin C9 peptide induces receptor internalization through a clathrin-independent pathway. Acta pharmacologica Sinica 29 24658352
2020 c9, t11, c15-CLNA and t9, t11, c15-CLNA from Lactobacillus plantarum ZS2058 Ameliorate Dextran Sodium Sulfate-Induced Colitis in Mice. Journal of agricultural and food chemistry 28 32125157
2020 Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS/FTD. Emerging topics in life sciences 28 32639008
2007 Molecular cloning, promoter analysis and induced expression of the complement component C9 gene in the grass carp Ctenopharyngodon idella. Veterinary immunology and immunopathology 28 17604124
2006 Mapping of the complement C9 binding domain in paramyosin of the blood fluke Schistosoma mansoni. International journal for parasitology 28 17123534
1999 Phosphorylation of the complement component, C9, by an ecto-protein kinase of human leukemic cells. Immunopharmacology 28 10408378
1996 Perforant path transection induces complement C9 deposition in hippocampus. Experimental neurology 28 8620918
2020 Glycoproteomic Analysis Reveals Aberrant Expression of Complement C9 and Fibronectin in the Plasma of Patients with Colorectal Cancer. Proteomes 26 32971853
1990 Comparison of channels formed by poly C9, C5b-8 and the membrane attack complex of complement. Molecular immunology 25 1696352
2022 C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect. Cells 23 36231090
2021 Polymerization of C9 enhances bacterial cell envelope damage and killing by membrane attack complex pores. PLoS pathogens 23 34752492
1999 Establishment of an inducible expression system of chimeric MLL-LTG9 protein and inhibition of Hox a7, Hox b7 and Hox c9 expression by MLL-LTG9 in 32Dcl3 cells. Oncogene 23 10023690
1997 The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure. Journal of immunology (Baltimore, Md. : 1950) 23 9144525
1992 IgA nephropathy in patients with congenital C9 deficiency. Kidney international 23 1453611
1991 DNA polymorphisms and linkage relationship of the human complement component C6, C7, and C9 genes. Immunogenetics 23 1672663
2006 Functional studies of the MACPF domain of human complement protein C8alpha reveal sites for simultaneous binding of C8beta, C8gamma, and C9. Biochemistry 21 16618117
1998 Reference typing report for complement components C6, C7 and C9 including mutations leading to deficiencies. Experimental and clinical immunogenetics 21 10072638
2015 c9, t11- conjugated linoleic acid induces HCC cell apoptosis and correlation with PPAR-γ signaling pathway. American journal of translational research 20 26885272
2014 Mapping of the complement C9 binding domain on Trichinella spiralis paramyosin. Parasites & vectors 20 24564979
2008 Association between activation of phase 2 enzymes and down-regulation of dendritic cell maturation by c9,t11-conjugated linoleic acid. Immunology letters 20 18343507
2003 Founder effect of the C9 R95X mutation in Orientals. Human genetics 20 12596049
1998 Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency. Human genetics 20 9703418
2000 Effect of C9-methyl substitution and C8-C9 conformational restriction on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines. Journal of medicinal chemistry 19 10956221
1987 Role of complement C9 and calcium in the generation of arachidonic acid and its metabolites from rat polymorphonuclear leukocytes. Molecular immunology 19 2828929
1985 Penetration of C8 and C9 in the C5b-9 complex across the erythrocyte membrane into the cytoplasmic space. The Journal of biological chemistry 19 2857173
2019 Multi-level engineering of Baeyer-Villiger monooxygenase-based Escherichia coli biocatalysts for the production of C9 chemicals from oleic acid. Metabolic engineering 18 30953778
2022 Nucleoporins are degraded via upregulation of ESCRT-III/Vps4 complex in Drosophila models of C9-ALS/FTD. Cell reports 17 36130523
2021 The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade. Human molecular genetics 17 33783477
2020 The dietary c9,t11-conjugated linoleic acid enriched from butter reduces breast cancer progression in vivo. Journal of food biochemistry 17 32030801
2016 Characterisation and expression analysis of two terminal complement components: C7 and C9 from large yellow croaker, Larimichthys crocea. Fish & shellfish immunology 17 26902705
2001 The human complement C9 gene: structural analysis of the 5' gene region and genetic polymorphism studies. European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics 17 11881818
2018 Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration. Human molecular genetics 16 29767720
2018 Osmotic and hypoxic induction of the complement factor C9 in cultured human retinal pigment epithelial cells: Regulation of VEGF and NLRP3 expression. Molecular vision 16 30090015
1989 Vitronectin colocalizes with Ig deposits and C9 neoantigen in discoid lupus erythematosus and dermatitis herpetiformis, but not in bullous pemphigoid. The British journal of dermatology 16 2474318
1989 The gene for human complement C9 is on chromosome 5. Genomics 16 2767685
2021 Evaluation of the immunomodulatory effects of C9-13-CPs in macrophages. Acta biochimica et biophysica Sinica 15 34355237
1995 The kinetics and distribution of C9 and SC5b-9 in vivo: effects of complement activation. Clinical and experimental immunology 15 7697921

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