Affinage

C5

Complement C5 · UniProt P01031

Round 2 corrected
Length
1676 aa
Mass
188.3 kDa
Annotated
2026-04-28
130 papers in source corpus 50 papers cited in narrative 51 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Complement C5 is a central effector of innate immunity whose proteolytic cleavage generates two functionally distinct arms of the terminal complement pathway: the anaphylatoxin C5a and the MAC-initiating fragment C5b. C5 is cleaved by C5 convertases whose specificity is allosterically switched from C3 to C5 by increasing C3b surface density (>1000-fold Km shift), and also by non-complement serine proteases from activated phagocytes and cancer cells (PMID:12440962, PMID:12414531, PMID:25050844). C5a signals through the Gi-coupled receptor C5aR1 (activating Ras/Raf/MEK/ERK and PI3K/Akt cascades) to drive neutrophil chemotaxis, mast cell migration, inflammasome priming, Fcγ receptor rebalancing, and platelet CXCL4 release, while C5aR2 modulates this signaling as both an endothelial transcytosis receptor delivering C5a into the vascular lumen and a negative regulator of C5aR1 via β-arrestin interaction (PMID:8090790, PMID:31076525, PMID:24179165). C5b sequentially recruits C6 and C7 through its α′-chain cysteine-rich domains to form membrane-inserted MAC (C5b-9), which at sublytic concentrations activates ERK, PI3K/Akt, and cell-cycle entry independently of C5a signaling (PMID:1387399, PMID:15855657, PMID:11414362).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1969 High

    Identification that C5 cleavage generates a potent leukocyte chemoattractant (C5a) established the first effector function of C5 beyond hemolysis and linked complement activation to cellular immune recruitment.

    Evidence In vitro chemotaxis assay with C5-derived fractions from human serum

    PMID:5765461

    Open questions at the time
    • C5a structure unknown
    • receptor identity unknown
    • mechanism of C5 cleavage specificity unresolved
  2. 1978 High

    Determination of the complete 74-residue primary structure of C5a, including three disulfide bonds and C-terminal Arg74 as critical for chemotactic potency, provided the first molecular framework for C5a pharmacophore studies.

    Evidence Protein sequencing, carbohydrate analysis, and functional chemotaxis assays of purified human C5a

    PMID:342601 PMID:690134

    Open questions at the time
    • Three-dimensional structure undetermined
    • receptor binding residues beyond Arg74 unknown
  3. 1985 High

    Identification of the C5a receptor on neutrophils (~40 kDa binding moiety) by affinity cross-linking demonstrated a specific, saturable receptor distinct from other chemoattractant receptors, and NMR studies confirmed the predicted four-helix bundle core of C5a.

    Evidence 125I-C5a affinity cross-linking with SDS-PAGE on human PMN; 3D heteronuclear NMR of 15N-labeled recombinant C5a

    PMID:2730871 PMID:3997862

    Open questions at the time
    • Receptor primary sequence unknown
    • G-protein coupling mechanism uncharacterized
  4. 1986 High

    Reconstitution of C5b-6/C5b-7 membrane insertion with defined lipid vesicles revealed that C6 and C7 bind the C5b α′-chain and that negatively charged phospholipids are required for initial membrane association, defining the assembly pathway of the MAC.

    Evidence Lipid vesicle binding assays, bimolecular kinetics, and activation energy measurements with purified complement components

    PMID:3801440

    Open questions at the time
    • Full MAC (C5b-9) assembly and pore structure unresolved
    • membrane insertion mechanism of C8/C9 not addressed
  5. 1991 High

    Cloning of C5aR revealed it as a seven-transmembrane GPCR, immediately explaining its Gi-dependent signaling properties and enabling targeted genetic and pharmacological studies.

    Evidence cDNA cloning from U937/HL-60 cells, heterologous expression in COS-7 cells with radioligand binding confirmation

    PMID:1847994

    Open questions at the time
    • Downstream signaling cascades not yet mapped
    • second C5a receptor (C5L2/C5aR2) unknown
  6. 1994 High

    Systematic mutagenesis of C5a defined a two-domain pharmacophore (10 charged core residues + C-terminal Arg74, with Lys19/20 critical), while C5aR signaling was mapped to Gi-coupled Ras/Raf/MEK/ERK and PKC-dependent pathways, connecting ligand structure to intracellular signaling architecture.

    Evidence Site-directed mutagenesis with Ca2+ mobilization and receptor binding; kinase activity assays with pertussis toxin and PKC modulators in neutrophils

    PMID:7987211 PMID:8090790 PMID:8112341

    Open questions at the time
    • Structural basis of C5a-C5aR interaction at atomic resolution not yet available
    • receptor phosphorylation/desensitization cycle incomplete
  7. 1995 High

    Discovery that C5aR undergoes GRK-mediated phosphorylation (Gi-independent) and requires PP1/PP2A-dependent dephosphorylation for recycling/resensitization defined the regulatory cycle controlling C5a responsiveness.

    Evidence 32P-phosphorylation, pertussis toxin, okadaic acid treatment, and receptor trafficking kinetics in differentiated HL-60 cells

    PMID:7706744

    Open questions at the time
    • Specific GRK isoform identity unresolved
    • phosphorylation sites on C5aR not mapped
  8. 2001 High

    Identification of C5aR N-terminal tyrosine sulfation (Tyr11, Tyr14) as essential for C5a docking, combined with the finding that sublytic MAC activates ERK/PI3K/Akt and cell-cycle entry, established two-site receptor engagement and separated the signaling roles of C5a and C5b-9.

    Evidence 35S-sulfate labeling and mutagenesis of C5aR with functional assays; ERK/Akt kinase assays and cell-cycle analysis after sublytic MAC treatment

    PMID:11342590 PMID:11414362

    Open questions at the time
    • Atomic-resolution structure of C5a–C5aR complex not yet solved
    • MAC signaling receptor identity unclear
  9. 2002 High

    C5 convertase specificity was quantitatively explained by C3b surface density (>1000-fold Km shift), while phagocyte-derived serine proteases were shown to generate C5a independently of complement convertases, revealing parallel activation pathways for C5.

    Evidence Km determination for reconstituted convertases at varying C3b densities; incubation of activated phagocytes with C5 plus serine protease inhibitor panels

    PMID:12414531 PMID:12440962

    Open questions at the time
    • Identity of phagocyte serine protease not determined
    • structural basis of C3b density-dependent allosteric switch unknown
  10. 2003 High

    Discovery that C5L2/C5aR2 binds C5a with high affinity but is obligately G-protein-uncoupled (DRY→DLC mutation), combined with genetic evidence that C5a/C3a drive liver regeneration via NF-κB/STAT-3, expanded C5 biology beyond immunity into regeneration and defined a second, non-signaling receptor.

    Evidence Pharmacological characterization of C5L2 (radioligand binding, cAMP, Ca2+, MAPK); complement-deficient mice with partial hepatectomy and C3a/C5a reconstitution

    PMID:12899627 PMID:12975457

    Open questions at the time
    • C5L2 in vivo function unclear
    • mechanism of C5a-driven hepatocyte proliferation beyond cytokine induction not mapped
  11. 2005 High

    Genetic mapping of C5 (Hc locus) as the causal gene for hepatic fibrosis susceptibility, validated by transgenesis and C5aR antagonist treatment, established C5a-C5aR as a therapeutic target in fibrotic disease.

    Evidence Congenic mice, BAC transgenesis, C5aR small-molecule antagonist in vivo, human hepatitis C genetic association

    PMID:15995705

    Open questions at the time
    • Fibrogenic cell type responding to C5a not definitively identified
    • mechanism of C5a-driven stellate cell activation unresolved
  12. 2007 High

    C5L2/C5aR2 was shown to have non-redundant pro-inflammatory roles in vivo (facilitating C5a signaling, mediating HMGB1 release in sepsis), resolving the initial characterization as merely a decoy receptor.

    Evidence C5L2-KO mice in LPS sepsis, OVA airway inflammation, and CLP sepsis models; HMGB1 ELISA; dual C5aR1/C5aR2 blockade

    PMID:17322907 PMID:18454156

    Open questions at the time
    • Mechanism by which C5aR2 signals without G-protein coupling not defined
    • cell-type-specific roles of C5aR2 (macrophage vs. endothelium) not delineated
  13. 2014 High

    Discovery of the C5 p.Arg885His variant that retains hemolytic function but abolishes eculizumab binding explained clinical resistance in PNH patients, demonstrating that therapeutic anti-C5 antibodies target a defined epitope distinct from the convertase cleavage or MAC-assembly sites.

    Evidence Gene sequencing, hemolysis assays with mutant C5, eculizumab and N19-8 binding assays in PNH patient-derived samples

    PMID:24521109

    Open questions at the time
    • Precise structural basis of eculizumab–C5 interaction not yet resolved at atomic level at this time
    • frequency of resistance variants in non-Asian populations unclear
  14. 2016 High

    Crystal structures of C5 bound to three structurally distinct inhibitors (tick OmCI-class proteins, eculizumab Fab) at non-overlapping sites—all blocking convertase activation—established that C5 requires a conformational priming event for cleavage, not merely enzyme access to the scissile bond.

    Evidence X-ray crystallography of C5–inhibitor complexes with competitive convertase inhibition assays

    PMID:27018802

    Open questions at the time
    • Nature of the conformational priming event uncharacterized
    • C5 convertase–C5 complex structure not solved
  15. 2018 High

    Crystal structures of C5aR1 with orthosteric (PMX53) and allosteric (avacopan) antagonists revealed two druggable binding sites and a novel helix-8 conformation, providing the structural basis for rational C5aR1 drug design.

    Evidence X-ray crystallography of C5aR1 ternary complexes, computational docking, cell-based signaling assays

    PMID:29867214

    Open questions at the time
    • Active-state C5aR1 structure with C5a not available
    • structural basis of biased agonism/antagonism at C5aR1 unknown
  16. 2019 High

    C5aR2 was revealed to function as a transcytosis receptor on endothelial cells, transporting C5a from tissue to vascular lumen to initiate C5aR1-mediated neutrophil arrest, while simultaneously acting as a negative regulator of C5aR1 via physical interaction with β-arrestin—resolving the paradox of C5aR2's dual pro- and anti-inflammatory roles.

    Evidence Intravital microscopy with C5aR2-KO mice; co-immunoprecipitation of C5aR2–C5aR1–β-arrestin; MPO-ANCA GN model with receptor KOs

    PMID:24179165 PMID:31076525

    Open questions at the time
    • Structural basis of C5aR2 transcytosis mechanism unresolved
    • endothelial vs. leukocyte C5aR2 contributions not fully dissected
  17. 2023 High

    Phagocyte-intrinsic C5 production (not only liver-derived C5) was shown to be a critical substrate source for C5a-C5aR1 antifungal defense, with C5aR1 signaling promoting phagocyte survival via ERK/Akt/mTOR-dependent metabolic reprogramming.

    Evidence C5ar1-KO mice with systemic candidiasis, RNA-seq, metabolomics, mTOR pathway inhibition, phagocyte-specific C5 expression analysis

    PMID:37220746

    Open questions at the time
    • Protease responsible for phagocyte-autonomous C5 cleavage not identified
    • relative contribution of local vs. hepatic C5 in other infectious or inflammatory contexts unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of the C5 convertase–C5 complex (and the nature of the conformational priming event required for cleavage), the identity of the phagocyte serine protease that cleaves C5, the active-state structure of C5aR1 bound to C5a, and the receptor/mechanism by which sublytic MAC activates intracellular signaling.
  • C5 convertase–C5 complex structure not solved
  • Phagocyte C5-cleaving protease not identified
  • Active-state C5a–C5aR1 structure unavailable
  • MAC signaling receptor unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 6 GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 10 R-HSA-162582 Signal Transduction 6 R-HSA-109582 Hemostasis 2
Partners
C3BC5AR1C5AR2C6C7CFHR1
Complex memberships
C5b-6C5b-7MAC (C5b-9)

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1969 A neutrophil chemotactic factor was identified as a fragment derived from complement component C5 (C'5), establishing that C5 cleavage generates a potent leukocyte chemoattractant (C5a). In vitro chemotaxis assay with C5-derived fractions Journal of immunology High 5765461
1978 Complete primary structure of human C5a was determined: 74 amino acids with a single complex oligosaccharide at Asn64, three disulfide bonds, and a C-terminal Arg74 critical for chemotactic activity (removal as C5a-desArg reduces leukotaxis). Protein sequencing, carbohydrate analysis, functional chemotaxis assays The Journal of biological chemistry High 690134
1978 C3a and C5a were shown to be chemotactic for human leukocytes in vitro; C5a is substantially more potent than C3a as a leukocyte chemoattractant. In vitro leukotaxis assays; in vivo stimulated conditions Journal of immunology High 342601
1983 Limited cleavage of the C5 alpha-chain by non-complement proteases (trypsin, thrombin, plasmin, elastase) generates C5a-like biological activities (neutrophil enzyme release and chemotaxis) without releasing free polypeptide fragments; the cleaved fragments remain disulfide-bonded to the C5 molecule. In vitro proteolysis, SDS-PAGE, gel filtration, neutrophil functional assays The Journal of experimental medicine High 6222137
1985 The C5a receptor on human PMN was identified by affinity cross-linking with 125I-C5a; the receptor binding moiety has an apparent molecular mass of ~40 kDa (complex ~52 kDa), distinct from nonspecific proteins, and shows specificity for C5a over fMLP and LTB4. Affinity cross-linking with disuccinimidyl suberate, SDS-PAGE, competition binding The Journal of biological chemistry High 3997862
1985 A three-dimensional model of C5a was built by comparative modeling from the C3a crystal structure, predicting conservation of the 4-helix core while external residues differ; the model suggested a possible receptor-binding site on C5a. Comparative molecular modeling based on C3a crystal structure Science Low 3992245
1986 C5b-6 requires negatively charged phospholipids (phosphatidylglycerol or phosphatidic acid) for initial membrane binding; after forming C5b-7, the complex inserts into membranes of all phospholipid compositions with ~20-fold selectivity for small over large unilamellar vesicles. C6 and C7 associate preferentially with the alpha'-chain of C5b. Lipid vesicle binding assays, activation energy measurements, bimolecular kinetics Biochemistry High 3801440
1988 C5a des-Arg (lacking C-terminal Arg74) retains in vivo inflammatory activity in human skin (wheal-and-flare, neutrophil infiltration, mast cell degranulation) but is less potent than intact C5a, indicating the C-terminal arginine enhances but is not absolutely required for all biological activities. Intradermal injection in human volunteers, histological analysis, in vitro binding Journal of immunology High 3351304
1989 C5a receptors on human eosinophils display two populations (high-affinity Kd ~31 pM, ~17,500 sites/cell; low-affinity Kd ~100 nM), with a C5a-receptor cross-linked complex of ~60-65 kDa — larger than the neutrophil receptor complex (~52 kDa) — suggesting distinct receptor molecules on eosinophils versus neutrophils. 125I-C5a binding (Scatchard analysis), covalent cross-linking with DSS, SDS-PAGE, cyanogen bromide cleavage The Journal of biological chemistry High 2912983
1989 Three-dimensional NMR spectroscopy (3D heteronuclear 1H-15N) of uniformly 15N-labeled C5a was demonstrated, providing resonance assignments and distance constraints consistent with a 4-helix bundle core structure and a flexible C-terminus. 3D heteronuclear NMR spectroscopy with 15N-labeled recombinant C5a Biochemistry High 2730871
1991 The human C5a receptor was cloned from U937 and HL-60 cells; expression in COS-7 cells confirmed high-affinity C5a binding. The deduced amino acid sequence revealed seven hydrophobic transmembrane domains, placing C5aR in the G-protein-coupled receptor superfamily. cDNA cloning, heterologous expression in COS-7 cells, radioligand binding Nature High 1847994
1992 The structure of complement C5b-7 was elucidated: plasmin cleaves C5b's alpha'-chain into C5c (Mr 142,000) and C5d (Mr 43,000); antibodies to C5c block C5b-6 interaction with C7, while antibodies to C5d inhibit C5 binding to C3b; chemical cross-linking showed both C6 and C7 associate preferentially with the alpha'-chain of C5b, and the C-terminal cysteine-rich domains of C6 and C7 bind specifically to C5. Limited proteolysis, circular dichroism, polyclonal antibody blocking, chemical cross-linking, solid-phase binding assays The Journal of biological chemistry High 1387399
1993 Terminal complement complexes C5b-7, C5b-8, and C5b-9 (MAC) generate non-lethal cellular signals including Ca2+ influx and second messengers (cAMP, inositol phosphates, arachidonate metabolites) in a cell-type-specific manner, demonstrating signaling functions of the MAC beyond cytolysis. Cell signaling assays, ion flux measurements, second messenger quantification in specific cell types Immunologic research Medium 8288945
1994 C5a receptor activation in human neutrophils signals through Gi proteins to activate both B-Raf and Raf-1 (with temporally distinct kinetics), MEK-1, and MAP kinase, as well as Ras (via guanine nucleotide exchange); both PKC-dependent and -independent pathways contribute, and PKA activation inhibits Raf. Kinase activity assays, Ras GTP-loading assay, pertussis toxin (Gi inhibition), PKC modulators, cAMP/PKA manipulation in human neutrophils Proceedings of the National Academy of Sciences of the United States of America High 8090790
1994 Site-directed mutagenesis of recombinant human C5a identified 10 non-contiguous charged amino acids in the 4-helix core plus the C-terminal Arg74 as comprising the pharmacophore; Arg74 substitution produced the largest single reduction in receptor binding and Ca2+ mobilization; C3a/C5a hybrid analysis confirmed the two-domain pharmacophore model. Site-directed mutagenesis, receptor binding assay, intracellular Ca2+ mobilization assay Protein science High 7987211
1994 Mutagenesis of human C5a confirmed that Lys19 and/or Lys20 are critical receptor-interacting residues (>30-fold activity loss on double replacement), while Arg40 and Pro45 replacements had little effect; des-Arg74 C5a retains C5aR activation in Xenopus oocytes but is inactive in the guinea pig ileum assay, revealing species-specific receptor differences. Site-directed mutagenesis, myeloperoxidase-release assay from granulocytes, Xenopus oocyte expression, CD spectroscopy for structural integrity European journal of biochemistry High 8112341
1994 C5a receptors on C5aR-deficient mice revealed that the C5a receptor is required for non-redundant mucosal host defence; C5aR knockout mice failed to clear Pseudomonas aeruginosa despite increased neutrophil influx, indicating C5aR controls neutrophil effector function rather than merely recruitment. C5aR gene disruption (knockout mice), intrapulmonary bacterial challenge, bacterial clearance assays, neutrophil quantification Nature High 8779720
1995 Agonist-occupied C5aR is phosphorylated by a G protein-coupled receptor kinase independently of Gi activation (pertussis toxin-insensitive); receptor dephosphorylation by PP1/PP2A-type phosphatases (okadaic acid-sensitive) is required for recycling of internalized C5aR back to the plasma membrane, suggesting dephosphorylation enables receptor resensitization. 32P-phosphorylation assays, pertussis toxin treatment, okadaic acid (phosphatase inhibitor), receptor internalization/recycling kinetics in differentiated HL60 cells Journal of immunology High 7706744
1997 C3a and C5a are chemotactic factors for human mast cells (HMC-1 line, cord blood-derived mast cells, cutaneous mast cells); migration requires extracellular matrix (laminin), is dose-dependent, inhibited by specific antibodies, and blocked by pertussis toxin indicating Gi protein coupling; both anaphylatoxins also mobilize intracellular Ca2+ in mast cells. Chemotaxis assays on laminin matrix, pertussis toxin treatment, calcium imaging with Fura-2 Blood High 9108406
2000 In renal ischemia/reperfusion injury, C5-deficient and C6-deficient (but not C4-deficient) mice are protected, and C6-deficient mice treated with anti-C5a showed no additional protection; reconstitution of C6 alone restored injury in C6-deficient mice. This demonstrates that the membrane attack complex (C5b-9, requiring both C5 and C6) rather than C5a-mediated neutrophil infiltration is the predominant mediator of renal I/R injury. Complement-deficient mouse models, renal artery occlusion model, histology, functional assays, antibody neutralization, reconstitution experiments The Journal of clinical investigation High 10811844
2001 Sublytic C5b-9 (MAC) activates the cell cycle and promotes cell survival via Gi-mediated ERK1/2 activation and PI3K/Akt pathway, which inhibits apoptosis through regulation of BAD; C5b-9 also reverses differentiated phenotype of postmitotic cells such as oligodendrocytes. Cell cycle analysis, kinase activity assays (ERK, PI3K/Akt), apoptosis assays, differentiation markers Immunological reviews Medium 11414362
2001 Tyrosines at positions 11 and 14 of the C5aR N-terminal domain are post-translationally sulfated; these sulfate moieties are critical for C5a binding and Ca2+ mobilization. A C5aR variant lacking sulfation responds normally to a small peptide agonist but not to intact C5a, supporting a two-site model where the sulfated N-terminus mediates the initial docking interaction with C5a. Post-translational modification analysis, site-directed mutagenesis, 35S-sulfate labeling, Ca2+ mobilization assay, peptide inhibition assay The Journal of experimental medicine High 11342590
2001 Rainbow trout C5 (first non-human/mouse C5 cloning) shows ~60% similarity to human C5, is expressed as a single gene in liver, confirming evolutionary conservation of C5 structure and hepatic expression across vertebrates. cDNA library cloning, Northern blot, Southern blot, mass spectrometry of tryptic digests, protein purification Developmental and comparative immunology Medium 11356221
2001 Sublytic C5b-9 induces ERK activation in glomerular epithelial cells via Ras and, in part, PKC-dependent pathways; this ERK activation depends on actin cytoskeletal integrity (blocked by cytochalasin D and latrunculin B) and is attenuated by constitutively active RhoA and ROCK inhibition; ERK activation leads to phosphorylation of cytosolic PLA2 and MAPKAPK-2 but not Elk-1, and is functionally distinct from the cytotoxic pathway. Dominant-negative Ras, pharmacological inhibitors (cytochalasin D, latrunculin B, ROCK inhibitor), constitutively active RhoA overexpression, kinase phosphorylation assays American journal of physiology. Renal physiology High 15855657
2002 C5 convertase specificity is regulated by C3b deposition density: monomeric C3b-containing convertases have a Km for C5 of ~25 µM (poor C5 cleavage); deposition of additional C3b on cell surfaces creates C3b-C3b and C4b-C3b complexes that shift Km for C5 more than 1000-fold (below physiological C5 concentration), switching the enzyme from C3 to C5 cleavage and initiating MAC formation. In vitro enzyme kinetics (Km determination), cell surface complement activation assays, convertase assembly reconstitution Biochemical Society transactions High 12440962
2002 Activated phagocytic cells (neutrophils and alveolar macrophages) generate biologically active C5a from exogenous C5 via a serine protease-dependent mechanism that is sensitive to transcription/translation inhibitors in macrophages but only partially in neutrophils, indicating a novel complement-independent pathway for C5a generation by phagocytes. Incubation of phagocytes with C5, antibody detection of C5a, serine protease inhibitors (aprotinin), actinomycin D/cycloheximide treatment, chemotaxis bioassay The American journal of pathology High 12414531
2002 Carboxypeptidase R (thrombin-activatable fibrinolysis inhibitor, TAFI) cleaves the C-terminal Arg from C5a much more efficiently than the classical carboxypeptidase N, inactivating the anaphylatoxin; upregulation of proCPR in inflammatory states suggests CPR is a major physiological inactivator of C5a. In vitro enzyme assay with C5a octapeptide substrate, kinetic comparison of CPR versus CPN activity Microbiology and immunology High 11939578
2003 C5L2 (GPR77/C5aR2) is a high-affinity C5a binding protein that is obligately uncoupled from heterotrimeric G proteins due to a Leu-for-Arg substitution in the DRY sequence at the end of transmembrane segment 3; it shows weak phosphorylation, no MAP kinase activation, no Ca2+ flux, and no chemotaxis induction upon C5a binding, and it does not interact with C3a or C4a. Radioligand binding, G-protein coupling assays (cAMP, calcium flux), MAP kinase assays, phosphorylation assays, chemotaxis assay, microarray analysis of C5aR-KO vs. C5L2-only cells, sequence analysis of DRY motif Biochemistry High 12899627
2003 C3a and C5a anaphylatoxins are essential for liver regeneration: C3- or C5-deficient mice show high mortality and impaired regeneration after partial hepatectomy; combined deficiency is rescued by reconstitution with both C3a and C5a; C5aR signaling is required for IL-6/TNFα induction and NF-κB/STAT-3 activation in the early priming phase of hepatocyte proliferation. Complement-deficient mouse models, partial hepatectomy, cytokine ELISA, NF-κB/STAT-3 activation assays, reconstitution with recombinant C3a/C5a The Journal of experimental medicine High 12975457
2005 Complement factor C5 (encoded by the Hc gene) was identified as the quantitative trait gene underlying a hepatic fibrosis susceptibility locus; small molecule C5aR antagonists had antifibrotic effects in vivo, and common C5 haplotype polymorphisms associated with advanced fibrosis in human hepatitis C, establishing C5/C5a-C5aR as a causal pathway in fibrogenesis. In silico QTL mapping, congenic mice, transgenesis with recombined artificial chromosomes (BAC/YAC), C5aR antagonist treatment, human genetic association Nature genetics High 15995705
2006 C3a and C5a generated in drusen induce VEGF expression in retinal pigmented epithelium in vitro and in vivo; genetic ablation of C3aR or C5aR reduces VEGF, leukocyte recruitment, and choroidal neovascularization after laser injury, establishing C5a-C5aR signaling as a mechanistic link between complement activation and angiogenesis in AMD. VEGF ELISA from C5a/C3a-stimulated cells, C3aR/C5aR knockout mice, laser-induced CNV model, leukocyte recruitment quantification, antibody neutralization, pharmacological receptor blockade Proceedings of the National Academy of Sciences of the United States of America High 16452172
2007 C5L2 (GPR77) facilitates C5a signaling in neutrophils, macrophages, and fibroblasts in vitro and is required for optimal C5a-mediated inflammatory cell infiltration in vivo; C5L2-deficient mice are hypersensitive to LPS-induced septic shock, show reduced OVA-induced airway hyper-responsiveness, and are mildly delayed in hematopoietic regeneration after irradiation — phenotypes mirroring C3aR-deficient mice. Gene targeting (C5L2 KO mice), in vitro signaling assays in primary cells, in vivo LPS sepsis model, OVA airway inflammation model, gamma-irradiation hematopoiesis recovery Nature High 17322907
2008 C5ar (C5aR1) and C5l2 (C5aR2/GPR77) contribute synergistically to harmful outcomes in sepsis; C5l2 specifically is required for in vivo and in vitro release of HMGB1 in a C5ar-independent manner; combined blockade of both receptors is required for protection in high-grade sepsis. Cecal ligation and puncture (CLP) model, receptor knockout mice, anti-receptor antibody blockade, HMGB1 ELISA, cytokine profiling Nature medicine High 18454156
2009 C5a and C5a-desArg signal through C5aR on dorsal root ganglia neurons to induce Ca2+ influx and sensitize C-nociceptors to heat; C5a sensitizes heat-responsive C-fibers (lower threshold, more action potentials) and activates A-nociceptors; C5aR mRNA is expressed in DRG. In vivo intraplantar injection, in vitro skin-nerve preparation, Ca2+ imaging (Fura-2), RT-PCR for C5aR mRNA in DRG Pain High 20031321
2012 Ischemic cortical neurons constitutively express C5 (the C5a precursor) and CD88 (C5aR); glucose deprivation or OGD increases C5a levels in culture media and upregulates CD88; exogenous C5a induces neuronal apoptosis; PMX53 (CD88 antagonist) or CD88 knockout reduces ischemia-induced apoptosis ~50%; CD88-KO mice have reduced infarct volumes after MCAO, demonstrating a local autocrine/paracrine C5a-CD88 apoptotic signaling loop in neurons. Primary neuronal culture, oxygen-glucose deprivation, C5a ELISA, CD88 antagonist (PMX53), CD88-KO mice, MCAO stroke model, infarct volume measurement FASEB journal High 22651932
2012 C5a promotes migration, proliferation, and 3D tube/ring formation of human microvascular endothelial cells (HMEC-1) in a dose-dependent manner via C5aR; C5aR antagonist W-54011 suppresses all these activities; Matrigel plug assay confirms pro-angiogenic effect in vivo. Cell cycle/proliferation assays (BrdU/FACS), Chemotaxicell migration assay, collagen gel ring formation, Matrigel plug in vivo, C5aR antagonist W-54011 Inflammation research High 20217457
2013 C5a selectively induces migration of STRO-1+/C5aR+ pulp progenitor cells via C5aR; perivascular localization of these progenitor cells was confirmed; C5aR antagonist W54011 blocks C5a-induced progenitor migration, and C5b-9 is detected in carious teeth, suggesting complement activation generates a C5a gradient that guides stem cell recruitment for dentin regeneration. Immunofluorescence, RT-PCR on STRO-1-sorted cells, C5aR antagonist-blocked migration assays, immunohistochemistry for C5b-9 Journal of dental research Medium 23603337
2013 Lung cancer cells constitutively produce C5a from C5 via a membrane-bound serine protease (sensitive to aprotinin and a furin-like inhibitor but not cysteine, acid, or metalloprotease inhibitors); this C5a acts on C5aR-expressing cancer cells to enhance invasion in vitro. C5a ELISA from conditioned media, serine protease inhibitor panel (aprotinin, RVKR-cmk), invasion assay, anti-C5a antibody neutralization Oncology reports Medium 25050844
2014 A heterozygous C5 missense mutation p.Arg885His (c.2654G→A), present in ~3.2% of Japanese and Han Chinese individuals, generates functionally active C5 that causes hemolysis normally but fails to bind eculizumab; this variant accounts for poor response to eculizumab in PNH patients. A second binding antibody (N19-8) targeting a different C5 epitope blocks both wild-type and mutant C5. Gene sequencing, in vitro hemolysis assay with mutant C5, eculizumab binding assay, N19-8 antibody blocking assay The New England journal of medicine High 24521109
2014 Porphyromonas gingivalis peptidylarginine deiminase (PPAD) citrullinates the critical C-terminal Arg74 of C5a, disabling its function: citrullinated C5a shows diminished neutrophil chemotaxis and reduced Ca2+ signaling via C5aR; P. gingivalis outer membrane vesicles generate fully citrullinated C5a (Arg74Cit) while PPAD-null vesicles do not. In vitro PPAD treatment of C5a, neutrophil chemotaxis assay, Ca2+ imaging (Fura-2 AM) in U937/C5aR cells, mass spectrometry (citrullination mapping), outer membrane vesicle treatment of C5 The Journal of biological chemistry High 25324545
2015 Neutrophil-derived phosphatidylserine-positive microvesicles suppress C5a-mediated priming of the NLRP3 inflammasome (reducing IL-1β release and neutrophil influx) via the PS-receptor MerTK; in a murine MSU peritonitis model, C5a generated after MSU injection primes the inflammasome, and PMN-derived ectosomes (generated in response to C5a) act as a negative-feedback autoregulatory loop requiring C5aR on resident cells. C5aR-KO mice, MerTK-KO mice, MSU peritonitis model, IL-1β ELISA, PS-liposome functional mimics, human joint aspirate ectosomes Annals of the rheumatic diseases High 26245757
2016 Three crystal structures of C5 in complex with distinct tick-derived inhibitors (OmCI, a second OmCI-class inhibitor, and eculizumab Fab) reveal three non-overlapping binding sites on C5 that all prevent its activation by C5 convertases; all three complexes competitively inhibit the C5 convertase, inconsistent with simple steric blockade and suggesting a priming/conformational event is required for C5 activation. X-ray crystallography of C5-inhibitor complexes, cryo-EM, competitive inhibition assays of C5 convertase Nature structural & molecular biology High 27018802
2018 Two crystal structures of human C5aR in ternary complexes reveal orthosteric action of the peptide antagonist PMX53 (stabilizing the C5aR structure) and allosteric binding of non-peptide antagonists (avacopan and NDT9513727) at a distinct intracellular allosteric site with different binding poses; helix 8 adopts a novel conformation relevant to C5aR activation. X-ray crystallography of C5aR ternary complexes, computational docking, biophysical binding assays, cell-based signaling assays Nature structural & molecular biology High 29867214
2019 C5aR2 (the 'atypical' C5a receptor) expressed on endothelial cells transports C5a from tissue into the vessel lumen via a transcytosis-like mechanism (intravital microscopy); this transported C5a is required to initiate C5aR1-mediated neutrophil arrest, while ACKR1 transports chemokines for CXCR2-dependent transendothelial migration — defining distinct roles for the two transport receptors in sequential steps of neutrophil recruitment. Intravital microscopy in live mice, immune complex arthritis model, C5aR2-KO and ACKR1-KO mice, fluorescent C5a tracking Science immunology High 31076525
2019 C5aR2 physically interacts with C5aR1 and β-arrestin to negatively modulate C5aR1 signaling; in an MPO-ANCA GN model, C5aR2 deficiency worsens disease while C5aR1 deficiency ameliorates it, demonstrating that C5aR1 engagement enhances inflammation and C5aR2 engagement suppresses inflammation in the same in vivo context. C5aR2-KO, C5aR1-KO, and human C5aR knock-in mice; MPO-ANCA GN model; CCX168 (C5aR1 antagonist) oral administration; co-immunoprecipitation of C5aR2-C5aR1-β-arrestin complex Journal of the American Society of Nephrology High 24179165
2019 A CirpT inhibitor from tick saliva binds directly to the peripheral MG4 domain of C5 (solved by cryo-EM at the full-C5 level and X-ray crystallography of C5_MG4-CirpT at 2.7 Å); this interaction prevents C5 activation by competitively inhibiting the C5 convertase, providing structural evidence that the MG4 domain is functionally important for convertase-mediated C5 activation. Cryo-electron microscopy (C5-CirpT complex), X-ray crystallography (C5_MG4-CirpT at 2.7 Å), direct binding assays, convertase inhibition assay Proceedings of the National Academy of Sciences of the United States of America High 31871188
2021 C5a-C5aR1 activation on platelets induces preferential release of CXCL4 (PF4), an antiangiogenic factor; platelet-specific C5aR1 deletion produces a proangiogenic phenotype with increased collateralization and capillarization; growth factor- and hypoxia-driven vascularization is markedly increased in global C5ar1-/- mice; interfering with the C5aR1-CXCL4 axis reverses the antiangiogenic platelet effect in vitro and in vivo. Platelet-specific C5aR1 KO mice, global C5ar1-/- mice, CXCL4 ELISA from C5a-stimulated platelets, endothelial cell migration/tube formation assays, in vivo angiogenesis models Nature communications High 34099640
2023 C5a-C5aR1 signaling promotes fungal clearance and host survival in systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent phagocyte survival in infected tissues; C5ar1 ablation rewires macrophage metabolism downstream of mTOR, promoting macrophage apoptosis. Critically, local C5 produced intrinsically by phagocytes (not only hepatocyte-derived C5) provides a key substrate for antifungal protection. C5ar1-KO mice, Candida infection model, RNA-seq, metabolomics, mTOR pathway inhibitors, phagocyte-specific C5 expression analysis, patient cohort correlation of C5a levels with outcome Cell High 37220746
1988 Complement C5 is the molecular basis of the hepatic fibrosis susceptibility QTL (Hc locus): congenic mice and BAC transgenesis with the Hc gene confirmed that C5 underlies fibrosis susceptibility; C5aR antagonist treatment had antifibrotic effects, linking C5 cleavage to C5a-C5aR-mediated fibrogenesis. Congenic mouse mapping, BAC transgenesis, C5aR antagonist in vivo treatment, liver fibrosis quantification Nature genetics High 15995705
2002 C5a anaphylatoxin regulates the activating/inhibitory FcγR balance on alveolar macrophages: C5a upregulates FcγRIII (activating) and downregulates FcγRII (inhibitory) via C5aR signaling; this bidirectional modulation is required for efficient cytokine production and neutrophil recruitment in immune complex-induced lung disease, connecting C5a to FcγR-complement crosstalk. FcγR expression by flow cytometry on alveolar macrophages, recombinant C5a stimulation, C5aR-KO and FcγRIII-KO mice, immune complex pulmonary model, cytokine ELISA The Journal of clinical investigation High 12488432
2009 CFHR1 (Factor H-related protein 1) inhibits complement C5 convertase activity and C5b surface deposition and MAC formation through a mechanism distinct from factor H (which inhibits C3 convertase); CFHR1 and factor H bind overlapping surface sites, suggesting sequential control of complement activation — factor H limits C3 convertase, CFHR1 limits C5 convertase/terminal pathway. C5 convertase activity assay (inhibition by CFHR1), C5b and MAC deposition assays on cell surfaces, competition binding with factor H Blood High 19528535

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 1778 24390342
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 Complement System Part I - Molecular Mechanisms of Activation and Regulation. Frontiers in immunology 1275 26082779
2010 Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature genetics 1018 20453842
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1988 Molecular organization and function of the complement system. Annual review of biochemistry 716 3052276
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2007 Complement C3 variant and the risk of age-related macular degeneration. The New England journal of medicine 690 17634448
2007 TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study. The New England journal of medicine 675 17804836
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2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
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2006 Drusen complement components C3a and C5a promote choroidal neovascularization. Proceedings of the National Academy of Sciences of the United States of America 534 16452172
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2003 An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nature medicine 512 14566334
2011 Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 405 22020285
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2003 The proinflammatory mediators C3a and C5a are essential for liver regeneration. The Journal of experimental medicine 335 12975457
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2007 Function, structure and therapeutic potential of complement C5a receptors. British journal of pharmacology 317 17603557
2008 Functional roles for C5a receptors in sepsis. Nature medicine 310 18454156
2014 Genetic variants in C5 and poor response to eculizumab. The New England journal of medicine 307 24521109
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2009 REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nature genetics 287 19503088
2013 C5a receptor (CD88) blockade protects against MPO-ANCA GN. Journal of the American Society of Nephrology : JASN 277 24179165
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2011 Inhibiting the C5-C5a receptor axis. Molecular immunology 240 21549429
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2002 C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. The Journal of clinical investigation 228 12488432
2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of infectious diseases 223 17703412
2007 A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS medicine 223 17880261
2009 Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 221 19528535
2005 Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nature genetics 211 15995705
2003 C5L2, a nonsignaling C5A binding protein. Biochemistry 211 12899627
2008 Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes and immunity 207 19110536
2007 C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature 187 17322907
2012 C3a and C5a promote renal ischemia-reperfusion injury. Journal of the American Society of Nephrology : JASN 182 22797180
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2008 Receptors for complement C5a. The importance of C5aR and the enigmatic role of C5L2. Immunology and cell biology 121 18227853
2010 The harmful role of c5a on innate immunity in sepsis. Journal of innate immunity 118 20588003
2018 Orthosteric and allosteric action of the C5a receptor antagonists. Nature structural & molecular biology 113 29867214
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2020 The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood 110 31978221
2001 Role of the C5b-9 complement complex in cell cycle and apoptosis. Immunological reviews 109 11414362
2016 Structural basis for therapeutic inhibition of complement C5. Nature structural & molecular biology 97 27018802
2012 Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 91 22651932
2002 Structure and function of complement C5 convertase enzymes. Biochemical Society transactions 88 12440962
2009 Functions of C5a receptors. Journal of molecular medicine (Berlin, Germany) 87 19189071
2004 Role of C5a-C5aR interaction in sepsis. Shock (Augusta, Ga.) 84 14676676
2023 C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection. Cell 83 37220746
2014 Peptidyl arginine deiminase from Porphyromonas gingivalis abolishes anaphylatoxin C5a activity. The Journal of biological chemistry 82 25324545
2010 Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine. PloS one 77 20808780
2001 Sulfated tyrosines contribute to the formation of the C5a docking site of the human C5a anaphylatoxin receptor. The Journal of experimental medicine 77 11342590
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2009 Nociceptive sensitization by complement C5a and C3a in mouse. Pain 70 20031321
2006 Drug evaluation: the C5a receptor antagonist PMX-53. Current opinion in molecular therapeutics 69 17243489
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2015 Neutrophil microvesicles resolve gout by inhibiting C5a-mediated priming of the inflammasome. Annals of the rheumatic diseases 67 26245757
2017 The Controversial C5a Receptor C5aR2: Its Role in Health and Disease. Journal of immunology research 65 28706957
2016 Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling. Immunology and cell biology 63 27108698
2012 New developments in C5a receptor signaling. Cell health and cytoskeleton 63 23576881
2014 Elevation of the terminal complement activation products C5a and C5b-9 in ALS patient blood. Journal of neuroimmunology 62 25262158
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2016 Complement-targeted therapy: development of C5- and C5a-targeted inhibition. Inflammation and regeneration 61 29259684
2012 New insights for C5a and C5a receptors in sepsis. Frontiers in immunology 61 23233853
2019 Critical role of C5a in sickle cell disease. American journal of hematology 60 30569594
2011 TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2. European journal of immunology 56 21630250
2020 Complement C5 Protein as a Marker of Subclinical Atherosclerosis. Journal of the American College of Cardiology 54 32327104
2014 Cancer cells release anaphylatoxin C5a from C5 by serine protease to enhance invasiveness. Oncology reports 54 25050844
2013 C3a, C5a renal expression and their receptors are correlated to severity of IgA nephropathy. Journal of clinical immunology 54 24327134
2015 A novel long non-coding RNA in the rheumatoid arthritis risk locus TRAF1-C5 influences C5 mRNA levels. Genes and immunity 53 26673966
2008 Protective effect of C5a receptor inhibition after murine reperfused stroke. Neurosurgery 53 18728577
2014 Direct decarboxylation of 5-carboxylcytosine by DNA C5-methyltransferases. Journal of the American Chemical Society 52 24716540
1989 Renal injury in DOCA-salt hypertensive C5-sufficient and C5-deficient mice. Kidney international 51 2681931
2022 Modulation of C5a-C5aR1 signaling alters the dynamics of AD progression. Journal of neuroinflammation 48 35820938
2013 Pulp progenitor cell recruitment is selectively guided by a C5a gradient. Journal of dental research 48 23603337
2013 Complement C3 and C5 deficiency affects fracture healing. PloS one 48 24260573
2021 The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets. Nature communications 47 34099640
2010 C5a promotes migration, proliferation, and vessel formation in endothelial cells. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 46 20217457
2023 The anaphylatoxin C5a: Structure, function, signaling, physiology, disease, and therapeutics. International immunopharmacology 45 36989901
2011 C5a regulates NKT and NK cell functions in sepsis. Journal of immunology (Baltimore, Md. : 1950) 45 22058413
2001 Structure/function of C5 convertases of complement. International immunopharmacology 45 11367526
2010 Inhibition of C5a receptor alleviates experimental CNS lupus. Journal of neuroimmunology 43 20207017
2014 Complement factor C5a induces atherosclerotic plaque disruptions. Journal of cellular and molecular medicine 42 25124749
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2011 Increased local concentration of complement C5a contributes to incisional pain in mice. Journal of neuroinflammation 40 21736743
2015 Retinal Pigment Epithelial Cells Mitigate the Effects of Complement Attack by Endocytosis of C5b-9. Journal of immunology (Baltimore, Md. : 1950) 39 26324770
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2019 Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation. Science immunology 38 31076525
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1995 Phosphorylation, dephosphorylation, and recycling of the C5a receptor in differentiated HL60 cells. Journal of immunology (Baltimore, Md. : 1950) 38 7706744
1999 Control of C3b and C5b deposition by CD46 (membrane cofactor protein) after alternative but not classical complement activation. European journal of immunology 36 10092084
2015 Orai1 controls C5a-induced neutrophil recruitment in inflammation. European journal of immunology 35 25912155
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2022 The anti-C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID-19. Clinical and translational science 33 35029045
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2018 Role of complement C5a and histones in septic cardiomyopathy. Molecular immunology 32 29914696
2005 Activation of the extracellular signal-regulated kinase by complement C5b-9. American journal of physiology. Renal physiology 32 15855657
1987 Leukocyte C5a receptor modulation during hemodialysis. Kidney international 32 2951551
1994 Phylogeny of the C3/C4/C5 complement-component gene family indicates that C5 diverged first. Molecular biology and evolution 31 8015436
2019 An inhibitor of complement C5 provides structural insights into activation. Proceedings of the National Academy of Sciences of the United States of America 30 31871188
2001 Expression of the anaphylatoxin C5a receptor in the oligodendrocyte lineage. Brain research 30 11251209
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2020 ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a. EMBO molecular medicine 29 32638512
2022 Involvement of complement peptides C3a and C5a in osteoarthritis pathology. Peptides 27 35598724
2015 CD4+ cells, macrophages, MHC-I and C5b-9 involve the pathogenesis of dysferlinopathy. International journal of clinical and experimental pathology 27 26045819
2008 Modeling molecular mechanisms of binding of the anaphylatoxin C5a to the C5a receptor. Biochemistry 27 18275159
1996 Elucidation of gene function using C-5 propyne antisense oligonucleotides. Nature biotechnology 27 9631067
2020 Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis. Anesthesiology 26 32101978