Affinage

C4B

Complement C4-B · UniProt P0C0L5

Length
1744 aa
Mass
192.8 kDa
Annotated
2026-04-28
100 papers in source corpus 52 papers cited in narrative 52 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C4B encodes the C4B isotype of complement component 4, a central effector of the classical and lectin complement pathways that, upon cleavage by activated C1, generates the opsonin C4b which covalently attaches to target surfaces preferentially via ester linkages—in contrast to C4A, which forms amide bonds and binds immune complexes more efficiently (PMID:3512717, PMID:3264881). Surface-deposited C4b nucleates C3 convertase assembly and recruits the alternative pathway by protecting nascent C3b from factor H/I–mediated inactivation, thereby amplifying complement activation (PMID:2148521, PMID:2247091). C4b activity is regulated by soluble C4b-binding protein (C4BP), a spider-shaped heptameric complex of alpha-chains (each bearing C4b-binding sites in CCP1–3) and one beta-chain (whose CCP1 binds protein S), which serves as cofactor for factor I–mediated cleavage of C4b; the C4BP–protein S complex additionally localizes complement regulation to apoptotic cell surfaces through protein S binding to phosphatidylserine (PMID:6480575, PMID:12440957, PMID:8702842, PMID:12193728). Numerous bacterial and viral pathogens—including N. gonorrhoeae, S. pyogenes, E. coli K1, C. albicans, S. pneumoniae, and flavivirus NS1—exploit C4BP by engaging distinct alpha-chain CCP modules to recruit its cofactor activity and evade complement-mediated killing (PMID:27595425, PMID:12444142, PMID:21642539, PMID:30323030).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1984 High

    Determining the ultrastructure of C4BP revealed how a multivalent regulator could simultaneously engage multiple C4b molecules, establishing the physical basis for its potent complement-inhibitory activity.

    Evidence Limited proteolysis and electron microscopy of purified C4BP showing seven tentacle subunits around a central core

    PMID:6480575

    Open questions at the time
    • Stoichiometry of simultaneous C4b engagement was not measured
    • No atomic-resolution structure of the full complex
  2. 1986 High

    Distinguishing the bond chemistry of C4A versus C4B isotypes explained their divergent biological roles: C4B's preference for ester linkages promotes efficient surface opsonization, while C4A's amide bonds favor immune complex handling.

    Evidence Chemical modification of erythrocyte amino groups, SDS-PAGE of radiolabeled C4 isotypes, and hemolytic assays with C2-deficient serum

    PMID:2937839 PMID:3512717

    Open questions at the time
    • Structural basis for the thioester reactivity difference between isotypes was not resolved
    • In vivo relevance of differential bond formation not directly tested
  3. 1988 High

    Identification of the C4BP beta-chain as the sole protein S–binding subunit resolved how C4BP bridges complement regulation and coagulation, and explained why beta-chain-lacking C4BP isoforms cannot sequester protein S.

    Evidence SDS-PAGE, gel filtration, chymotrypsin protection assays, and direct binding with subpopulation fractionation

    PMID:2532155 PMID:2970465

    Open questions at the time
    • Atomic contacts between beta-chain and protein S were unknown
    • Physiological regulation of beta-chain expression not yet addressed
  4. 1990 High

    Demonstrating that surface-deposited C4b protects nascent C3b from inactivation and recruits the alternative pathway convertase C3bBbP established the mechanism by which classical pathway activation amplifies through the alternative loop.

    Evidence In vitro reconstitution with purified complement components and hemolytic assays with defined component additions

    PMID:2148521 PMID:2247091

    Open questions at the time
    • Structural basis of C4b–C3b protective interaction not resolved
    • Relative contribution in vivo versus lectin pathway-deposited C4b unknown
  5. 1996 High

    Domain-swap chimeras localized the protein S–binding site to SCR-1 (CCP1) of the C4BP beta-chain, while mutagenesis mapped the C4b-binding site to positively charged residues at the CCP1–2 interface of the alpha-chain, defining the two principal functional surfaces of C4BP.

    Evidence Recombinant alpha/beta-chain chimeras with quantitative binding assays, and site-directed mutagenesis with complement functional assays

    PMID:12440957 PMID:8702842

    Open questions at the time
    • High-resolution co-crystal of C4BP–C4b complex not available
    • Role of CCP3 in C4b binding mechanism unclear
  6. 2002 High

    Discovery that protein S targets the C4BP–protein S complex to phosphatidylserine on apoptotic cells revealed a mechanism for localizing complement regulation to dying cells, preventing inflammatory complement activation during apoptotic clearance.

    Evidence Binding assays on apoptotic Jurkat cells blocked by annexin V and anti-Gla domain antibodies

    PMID:12193728

    Open questions at the time
    • Whether this mechanism is sufficient to prevent autoimmunity in vivo was not tested
    • Contribution relative to other apoptotic complement regulators (e.g., MCP) unresolved
  7. 2003 High

    The unexpected finding that C4BP alpha-chain binds CD40 on B cells and induces proliferation, costimulatory molecule upregulation, and IgE class switching revealed a non-complement immune-modulatory function of C4BP.

    Evidence Direct binding assays, B-cell proliferation/differentiation assays with CD40-deficient and NEMO-deficient patient cells, germinal center colocalization

    PMID:12818164

    Open questions at the time
    • Structural basis of C4BP–CD40 interaction unknown
    • In vivo contribution to B-cell responses not tested
    • Whether this function is altered during acute phase response when alpha-chain-only C4BP rises
  8. 2001 High

    Systematic mapping of pathogen exploitation of C4BP established that diverse bacteria and fungi bind distinct CCP modules of the alpha-chain (CCP1–2 for N. gonorrhoeae pili and C. albicans; CCP3 for E. coli OmpA; CCP2/5/7 for M. catarrhalis) to recruit functional C4BP and evade complement killing.

    Evidence Flow cytometry, recombinant C4BP CCP deletion mutants, competition assays, and serum bactericidal assays across multiple pathogen systems

    PMID:11359834 PMID:12444142 PMID:15383594 PMID:15501796

    Open questions at the time
    • Whether therapeutic blockade of specific CCPs could prevent immune evasion without disabling complement regulation
    • Evolutionary arms race dynamics between pathogen ligands and C4BP polymorphisms not characterized
  9. 2016 High

    Crystal structures of Group A Streptococcus M proteins bound to C4BP CCP1–3 revealed a conserved 'reading head' mechanism by which C4BP recognizes hidden sequence patterns in hypervariable M protein regions, explaining how ~90% of M types exploit C4BP.

    Evidence Crystal structures of four M protein–C4BP complexes with functional binding validation

    PMID:27595425

    Open questions at the time
    • Whether this reading head is also exploited by non-streptococcal pathogens
    • No structure of full-length heptameric C4BP bound to M protein
  10. 2023 High

    CryoEM visualization of C1-activated IgG3 hexameric platforms combined with mass spectrometry identification of C4b deposition sites on IgG3 Fab-proximal residues established the spatial geometry of nascent C4b covalent attachment during classical pathway initiation.

    Evidence CryoEM structure of IgG3-antigen-C1 complexes and MS identification of C4b attachment sites

    PMID:37419978

    Open questions at the time
    • Whether the same attachment geometry applies to IgG1/IgG2-initiated activation
    • Structural basis for C4b transition to C3 convertase on the antibody platform not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete atomic-resolution structure of the full heptameric C4BP in complex with C4b, and the structural basis for how C4BP serves simultaneously as factor I cofactor and alternative pathway regulator, remain unresolved.
  • No full-length cryo-EM or crystal structure of heptameric C4BP–C4b complex
  • Mechanism by which C4BP discriminates lectin vs. classical pathway-deposited C4b at the structural level is unknown
  • In vivo validation of C4BPA mutations (R120H, I126T, G423T) as causative for recurrent miscarriage awaits larger cohorts and animal models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 6 R-HSA-1643685 Disease 3 R-HSA-109582 Hemostasis 2
Partners
C2C3C4BPAC4BPBCD40CFICR1PROS1
Complex memberships
C4BP–protein S complexC4b-binding protein (C4BP) complexClassical pathway C3 convertase (C4b2a)

Evidence

Reading pass · 52 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 C4b-binding protein (C4BP) has a spider-like ultrastructure composed of seven identical disulfide-linked tentacle subunits (~70 kDa each) arranged around a central ringlike core (~160 kDa), as revealed by electron microscopy of chymotrypsin-generated fragments. Limited proteolysis + electron microscopy The Journal of biological chemistry High 6480575
1985 C4BP belongs to a multi-gene family of C3b/C4b-binding regulatory proteins that share a common ~60-amino-acid short consensus repeat (SCR/CCP) structural element, including factor H, CR1, DAF, and C2/factor B. Amino acid and nucleotide sequencing, structural comparison Immunology today High 25289982
1986 C4B isotype binds predominantly via ester linkages to cell surfaces, while C4A preferentially forms amide bonds; C4B deposited during classical pathway activation can activate the alternative complement pathway. Chemical modification of erythrocyte amino groups, SDS-PAGE of radiolabeled C4 isotypes on multiple cell lines; hemolytic assays with C2-deficient serum and Mg-EGTA conditions Journal of immunology / Journal of immunology High 2937839 3512717
1987 The protein S-binding site on C4BP is located in the central core (~160 kDa chymotrypsin fragment), not the tentacles, and requires intact disulfide bonds; protein S protects this site from proteolysis. Chymotrypsin proteolysis, immunoblotting with polyclonal antisera, direct binding assay The Journal of biological chemistry High 2956264
1988 A novel ~45 kDa beta-chain subunit in C4BP is directly involved in protein S binding; chymotrypsin cleavage of this subunit abolishes protein S binding, and protein S protects the beta-chain from proteolysis. SDS-PAGE, gel filtration in 6M guanidine HCl, chymotrypsin protection assay, N-terminal sequencing The Journal of biological chemistry High 2970465
1988 The protein S-binding site on C4BP maps to a peptide near the C-terminus of the alpha-chain core (residues Ser447–Tyr467), identified by monoclonal antibody MFbp16 affinity chromatography and competition binding with protein S. Chymotrypsin digestion, affinity chromatography on MFbp16-Sepharose, competition binding assay The Journal of biological chemistry Medium 2460456
1988 C4A3 binds immunoglobulins (IgG, IgM, IgA) in the fluid phase approximately 3–4 times more efficiently than C4B1, with C4A forming predominantly amide linkages and C4B1 forming both amide and ester bonds. Fluid-phase binding assay with purified C4, C1s and antibody; covalent bond characterization Molecular immunology High 3264881
1989 C4BP circulates in plasma as two subpopulations: a major form (seven alpha-chains + one beta-chain) that binds protein S, and a minor form lacking the beta-chain that cannot bind protein S, establishing the beta-chain as the sole protein S binding subunit. Subpopulation isolation, SDS-PAGE, direct protein S binding assay FEBS letters High 2532155
1989 C4BP synthesis and secretion is induced by IL-6 and TNF-α in the HepG2 hepatoma cell line, and plasma C4BP levels are elevated in acute pneumonia patients, establishing C4BP as an acute phase protein. Cell culture with cytokine stimulation, plasma measurements in pneumonia patients Biochemical and biophysical research communications Medium 2480119
1990 Nascent C3b covalently attaches to C4b, and C3b in C4b–C3b complexes is protected from inactivation by factors H and I, providing a mechanism by which classical pathway activation recruits and amplifies the alternative pathway. In vitro reconstitution with purified complement components, kinetic protection assays, surface plasmon resonance-type binding European journal of immunology High 2148521
1990 C4b deposited on cell surfaces activates the alternative pathway by binding the C3 convertase C3bBbP through a C3b interaction, amplifying C3b deposition; this requires C3b, properdin, factor B, and factor D but does not involve direct C4bBb formation. Hemolytic assays, radiolabeled component binding studies, C5-deficient serum experiments Molecular immunology High 2247091
1990 C4A is more effective than C4B in enhancing CR1-mediated binding of immune complexes to erythrocytes, whereas C4B is only modestly less efficient at inhibiting immunoprecipitation; the major functional difference between the isotypes is at the level of CR1 binding. CR1 binding assay with purified C4A and C4B, immune precipitation inhibition assay Clinical and experimental immunology High 2138067
1991 The C4BP alpha-chain gene spans >40 kb, is organized into 12 exons with each of the eight SCR repeats encoded by individual exons (except SCR2 which is split), and contains acute phase and liver-specific regulatory elements in its promoter region. Genomic cloning, exon mapping, sequence analysis, comparison with mouse C4BP alpha transcript The Journal of experimental medicine High 2022920
1991 C4BP beta-chain gene spans >10 kb, encodes three SCR domains plus a C-terminal non-repeat region, and produces two distinct mRNA classes from different transcription start sites; the alpha- and beta-chain genes are closely linked at chromosome 1q32. Genomic cloning, Northern blot, primer extension, S1 nuclease protection, cDNA isolation The Journal of biological chemistry High 8325877
1993 Protein S residues 413–434 (particularly the PSP-420 peptide, residues 420–434) are essential for binding to C4BP; a monoclonal antibody (LJ-56) against this region blocks complex formation and specifically recognizes free protein S but not the protein S:C4BP complex. Synthetic peptide inhibition assay, ELISA, polyclonal and monoclonal antibody inhibition studies The Journal of biological chemistry High 7688369
1994 Beta-chain residues 31–45 of C4BP (with the sequence YxLVG being critical) provide a protein S-binding site; peptide beta(31-45) inhibits the protein S:C4BP interaction and blocks protein S APC-cofactor activity. Synthetic peptide inhibition assays, surface plasmon resonance binding, coagulation assays The Journal of biological chemistry High 8300581
1994 Complement receptor CR1 (CD35) has two functional sites: site 1 (SCR1–2) binds C4b and serves as cofactor for C4b cleavage; site 2 (SCR8–9) binds primarily C3b but also C4b with greater cofactor activity for C4b cleavage than site 1. Substitution mutagenesis of CR1 constructs, binding assays, cofactor activity assays The Journal of biological chemistry High 8175757
1994 Murine C4BPB gene has become a pseudogene due to two in-frame stop codons, while the human gene is functional; this explains the absence of protein S binding by murine C4BP and reveals an evolutionary difference in the coagulation–complement interface. Genomic cloning, sequence analysis of multiple mouse strains, Southern blotting Genomics High 7959726
1995 Serum amyloid P component (SAP) binds to the central core of C4BP (not the tentacles) with high affinity (Kd ~30 nM) in a calcium-dependent, carbohydrate-dependent manner; the C4BP beta-chain is not required for SAP binding. SAP-Sepharose affinity chromatography, quantitative affinity chromatography, recombinant C4BP constructs The Journal of biological chemistry High 7592941
1995 IL-6, IL-1β, and IFN-γ differentially upregulate C4BPA and C4BPB gene expression in Hep3B cells; TNF-α downregulates both; IFN-γ combined with TNF-α produces a synergistic 10-fold induction of C4BP alpha-mRNA with minimal C4BP beta-mRNA increase, providing a mechanism to maintain C4BP beta homeostasis during acute phase response. Cytokine stimulation of Hep3B cells, Northern blot analysis of C4BPA and C4BPB mRNAs, analysis of C4BP isoforms in acute phase patient samples Journal of immunology High 7561114
1996 The entire protein S-binding site on C4BP resides within SCR-1 of the beta-chain; alpha/beta-chain chimeras replacing only SCR-1 of the alpha-chain with beta-chain SCR-1 confer full protein S binding affinity (Ka ~2.3×10⁸ M⁻¹). Recombinant alpha/beta chain chimera expression in eukaryotic cells, protein S binding assays The Journal of biological chemistry High 8702842
1998 The C4BP beta-chain SCR-1 interaction with protein S is primarily hydrophobic in nature, mediated by a solvent-exposed hydrophobic cluster; ionic interactions contribute minimally. Homology modeling, inter-species sequence comparison, binding studies with salt and detergent Biochimica et biophysica acta Medium 9774728
1998 Modeling of C4BP alpha-chain 8 CCP modules identified a cluster of positively charged residues at the CCP1–CCP2 interface as the principal binding site for C4b, heparin, and bacterial Arp/Sir proteins. Computer modeling combined with monoclonal antibody mapping and heparin binding experiments Proteins Medium 9626699
1999 Both G domains (G1 and G2) of the sex-hormone-binding globulin-like region of protein S contribute to C4BP binding; full-affinity binding requires both domains, with G1 contributing more than G2. Recombinant protein S/Gas6 chimeras, surface plasmon resonance, microtiter plate binding assays European journal of biochemistry High 10583388
1999 CR1 has a single C1q binding site on LHR-D; C1q and C4b bind CR1 independently and additively support erythrocyte adhesion, confirming CR1 as the receptor for all major complement opsonic ligands. BIAcore binding analysis, erythrocyte adhesion assay, anti-CR1 Fab inhibition Journal of immunology High 10528211
2001 Type IV pili of N. gonorrhoeae bind C4BP via the N-terminal part of PilC at CCP1 and CCP2 of the C4BP alpha-chain through ionic interactions; this binding overlaps only partially with the MCP (CD46) binding site on pili. Direct binding assay with isolated pili, C4BP mutants lacking individual CCPs, competition assays with C4b and NaCl titration Journal of immunology High 11359834
2002 Membrane cofactor protein (MCP/CD46) is the primary cofactor mediating C4b cleavage on MCP-expressing cells; fluid-phase C4BP does not significantly cleave cell-surface C4b in this model. For C3b deposited via the classical pathway, factor H is the primary cofactor. FACS and Western blotting on MCP-transfected cells, function-blocking monoclonal antibody, Mg-EGTA pathway-specific conditions Journal of immunology High 12055245
2002 OmpA of E. coli K1 binds the alpha-chain CCP3 of C4BP through hydrophobic interactions (not inhibited by C4b, heparin, or salt), recruiting C4BP to the bacterial surface and conferring serum resistance. Flow cytometry, CCP deletion mutants of recombinant C4BP, competition with synthetic CCP3 peptides, serum bactericidal assays Journal of immunology High 12444142
2002 Protein S mediates binding of C4BP to apoptotic cells by binding phosphatidylserine exposed on the apoptotic cell surface; this binding is calcium-dependent and blockable by annexin V, localizing complement regulatory activity to apoptotic cells. Binding assays with Jurkat apoptosis model, blocking with anti-PS Gla domain antibodies and annexin V, C4b interaction confirmation Journal of immunology High 12193728
2002 The C4b-binding site on C4BP requires CCP1–3 of the alpha-chain and is mediated by a cluster of positively charged amino acids at the CCP1–CCP2 interface; loss of C4b binding abolishes all classical pathway inhibitory activity of C4BP. Homology-based modeling, recombinant mutagenesis, complement functional assays Biochemical Society transactions High 12440957
2002 Protein S binding to C4BP is mediated by a cluster of surface-exposed hydrophobic amino acids on CCP1 of the beta-chain; heparin binding requires CCP1–3 of the alpha-chain with CCP2 being most important. Homology-based computer modeling, recombinant mutagenesis, binding assays Biochemical Society transactions High 12440957
2003 The alpha-chain of C4BP binds directly to CD40 on human B cells at a site distinct from CD40L, inducing B-cell proliferation, upregulation of CD54 and CD86, and IL-4-dependent IgE isotype switching; this effect requires CD40 and IKKγ/NEMO signaling. Direct binding assays, B-cell proliferation and differentiation assays, experiments with B cells from CD40- and IKKγ/NEMO-deficient patients, colocalization in germinal centers Immunity High 12818164
2003 Zinc at micromolar concentrations enhances C4BP cofactor activity toward C4b/C3b by increasing affinity between C4b/C3b and cofactor proteins; millimolar zinc concentrations inhibit cofactor activity by aggregating C4b/C3b. Cofactor activity assays, 65Zn binding studies, fluorescent chelator Kd measurements, surface plasmon resonance Archives of biochemistry and biophysics High 14522582
2004 M. catarrhalis UspA2 and UspA1 bind C4BP alpha-chain at CCP2, CCP5, and CCP7; surface-bound C4BP retains cofactor activity for C4b degradation, conferring serum resistance. Flow cytometry, RIA, recombinant UspA binding assays with C4BP deletion mutants, cofactor activity assay for C4b degradation Journal of immunology High 15383594
2004 C. albicans hyphal and yeast forms bind C4BP at CCP1–2 of the alpha-chain; surface-bound C4BP retains cofactor activity for C4b inactivation and mediates adhesion of C. albicans to host endothelial cells. Confocal microscopy, flow cytometry, ELISA, absorption from human serum, recombinant deletion constructs, monoclonal antibodies Infection and immunity High 15501796
2004 The C4BP–protein S complex inhibits phagocytosis of apoptotic cells by macrophages; free protein S enhances phagocytosis, but when complexed to C4BP, the protein S proengulfment activity is blocked while C4BP localizes to apoptotic cell surfaces via protein S. Phagocytosis assay with primary human macrophages and THP-1 cells, complement-depleted serum reconstitution, anti-Gla domain antibody blocking The Journal of biological chemistry High 15096498
2005 N. gonorrhoeae porin (Por) binds human C4BP in a species-specific manner to evade complement; Por1B-bearing strains bind chimpanzee C4BP but not rodent/lagomorph C4BP, explaining the host restriction of gonorrhea. Serum bactericidal assays with species-specific sera, C4BP binding studies, C4BP reconstitution in heterologous sera PNAS High 16275906
2006 CRP binds C4BP, with the binding site localized to the central core of C4BP; C4BP lacking beta-chain and protein S (an acute-phase form) binds CRP with higher affinity; C4BP–CRP complexes exist in patient serum and C4BP retains full complement regulatory activity in the presence of CRP. ELISA with recombinant CRP and phosphorylcholine-CRP, proteolytic C4BP fragment binding, ionic strength titration, patient serum analysis, complement activation assay Journal of immunology High 16751408
2007 Y. enterocolitica uses both YadA and Ail outer membrane proteins as C4BP receptors; Ail-mediated C4BP binding is blocked by O-antigen and outer core LPS. Surface-bound C4BP retains factor I-mediated C4b degradation activity. C4BP binding assays with LPS/protein mutant panel, flow cytometry, cofactor activity assay PLoS pathogens High 18769718
2007 N. gonorrhoeae Por1B selectively binds C4b via amide linkages (at loops 4–5) and C3b via ester linkages; all Opa proteins (A,B,C,D,E,F,I) bind both C4b and C3b; C4Ab preferentially forms monomers/heterodimers while C4Bb participates in C5 convertase heterodimer formation. Hybrid Por1A/1B molecule analysis, serum with only C4A isoform, Opa-specific variant strains, bond-type characterization Infection and immunity High 17984207
2008 C4BP binds Aβ1-42 peptide directly via the C4BP alpha-chain and localizes to amyloid plaques and apoptotic cells in Alzheimer's disease brain, limiting complement activation on these targets in vitro. Immunohistochemistry, in vitro binding assay with dead brain cells and Aβ1-42, complement activation assay Molecular immunology Medium 18556068
2009 C4BP binds directly to small leucine-rich repeat proteins (SLRPs: osteoadherin, chondroadherin, fibromodulin, PRELP) predominantly via its central core; C4BP binding does not impair complement inhibitory activity but limits C9 deposition activated by SLRPs in serum. Direct binding assays with C4BP fragments/mutants, electron microscopy, C9 deposition assay with C4BP-depleted serum Journal of immunology High 19155499
2009 C4BP regulates the lectin pathway C3/C5 convertase with ~7–13-fold greater affinity for C4b deposited via the lectin pathway than the classical pathway; at high C4b density, all seven alpha-chains of C4BP can simultaneously engage C4b. Reconstituted complement assays on zymosan and E(Man), stoichiometric analysis of C4b per C4BP Molecular immunology High 19660812
2011 Dengue, West Nile, and yellow fever virus NS1 directly binds C4BP with binding sites on NS1 that partially overlap the C4b-binding sites; soluble NS1 recruits C4BP to inactivate C4b in solution and on plasma membranes, representing a second complement-evasion mechanism. Direct binding assays, mapping studies with C4BP mutants, C4b inactivation assays on plasma membrane Journal of immunology High 21642539
2011 PTX3 binds C4BP at SCR1–3 of the C4BP alpha-chain; PTX3 does not compete with factor H for C4BP binding but is inhibited by C1q and L-ficolin; C4BP recruited by PTX3 on extracellular matrix or late apoptotic cells retains complement regulatory activity and reduces C5b-9 deposition. ELISA, competition binding assays, complement deposition assays on ECM and apoptotic cells PloS one High 21915248
2011 Candida Pra1 is the first fungal C4BP-binding protein; Pra1 binds C4BP at CCP4, CCP7, and CCP8 of the alpha-chain through ionic interactions; C4BP and factor H bind simultaneously to Pra1; surface-bound C4BP inhibits C4b and C3b deposition. ELISA, isothermal titration calorimetry, recombinant C4BP CCP deletion mutants, C4BP/factor H co-binding assays, C4b/C3b surface deposition assay The Journal of biological chemistry High 21212281
2012 Pneumococcal enolase binds C4BP at CCP1/CCP2 and CCP8 of the C4BP alpha-chain; C4BP and plasminogen bind distinct sites on enolase without competition; enolase-bound C4BP retains cofactor activity for C4b degradation. Dose-dependent binding assays, ionic strength titration, recombinant C4BP mutants lacking individual CCPs, C3b deposition assay, cofactor activity assay Journal of immunology High 22925928
2013 Mutations in C4BPA (R120H, I126T, G423T) found in women with recurrent miscarriage affect the expression level and/or factor I cofactor activity of C4BP, while a CD46 variant (N213I) causes deficient protein processing and impaired cofactor activity for both C4b and C3b. Sequencing, recombinant protein expression, cofactor activity assay for factor I European journal of immunology Medium 23508668
2016 C4BP uses a conserved 'reading head' in CCP1–3 to detect hidden conserved sequence patterns within the hypervariable M protein regions of Group A Streptococcus, enabling broad (~90% M type) recognition; crystal structures of four M proteins in complex with C4BP revealed a uniform binding mechanism. Crystal structure determination of four M protein–C4BP complexes, functional binding validation Nature microbiology High 27595425
2017 B. burgdorferi OspC directly binds complement component C4b and competes with complement protein C2 for C4b binding, thereby inhibiting classical and lectin pathway activation; this confers bloodstream survival in vivo. Direct binding assays, C2 competition assay, in vivo mouse bloodstream survival experiments Cellular microbiology High 28873507
2018 Pneumococcal PspA and PspC both bind serum C4BP; deletion of PspA or PspC reduces C4BP deposition on bacteria, increases C4b and iC4b deposition, and reduces C4dg, establishing that PspA and PspC sequester C4BP to inactivate C4b and evade complement. Targeted gene deletion, serum opsonization assays, recombinant PspA/PspC binding assays, mouse infection experiments Infection and immunity High 30323030
2023 CryoEM structures show that IgG3 forms elevated hexameric Fc platforms; mass spectrometry reveals that C1 (activated by IgG3) deposits C4b directly onto specific IgG3 residues proximal to the Fab domains, a consequence of the elevated height of the C1-IgG3 complex. CryoEM structure determination of IgG3-antigen-C1 complexes, mass spectrometry identification of C4b deposition sites Nature communications High 37419978

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Binding of flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation. Journal of immunology (Baltimore, Md. : 1950) 160 21642539
2004 Complement inhibitor C4b-binding protein-friend or foe in the innate immune system? Molecular immunology 155 15072852
2000 Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease. The Journal of experimental medicine 154 10859342
1988 Novel subunit in C4b-binding protein required for protein S binding. The Journal of biological chemistry 144 2970465
2002 A novel interaction of outer membrane protein A with C4b binding protein mediates serum resistance of Escherichia coli K1. Journal of immunology (Baltimore, Md. : 1950) 136 12444142
2002 Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells. Journal of immunology (Baltimore, Md. : 1950) 119 12055245
1986 Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein. The Journal of clinical endocrinology and metabolism 119 3007562
2015 C4b-binding protein: The good, the bad and the deadly. Novel functions of an old friend. Immunology letters 113 26658464
1985 Human C3b- and C4b-regulatory proteins: a new multi-gene family. Immunology today 110 25289982
2003 C4b-binding protein (C4BP) activates B cells through the CD40 receptor. Immunity 106 12818164
2023 Construction of Co4 Atomic Clusters to Enable Fe-N4 Motifs with Highly Active and Durable Oxygen Reduction Performance. Angewandte Chemie (International ed. in English) 105 37222657
2004 The emerging pathogen Moraxella catarrhalis interacts with complement inhibitor C4b binding protein through ubiquitous surface proteins A1 and A2. Journal of immunology (Baltimore, Md. : 1950) 103 15383594
2008 Yersinia enterocolitica serum resistance proteins YadA and ail bind the complement regulator C4b-binding protein. PLoS pathogens 96 18769718
2002 Vitamin K-dependent protein S localizing complement regulator C4b-binding protein to the surface of apoptotic cells. Journal of immunology (Baltimore, Md. : 1950) 96 12193728
1989 Protein S binding in relation to the subunit composition of human C4b-binding protein. FEBS letters 95 2532155
1994 Analysis of the functional domains of complement receptor type 1 (C3b/C4b receptor; CD35) by substitution mutagenesis. The Journal of biological chemistry 89 8175757
2006 Regulation of complement activation by C-reactive protein: targeting of the inhibitory activity of C4b-binding protein. Journal of immunology (Baltimore, Md. : 1950) 86 16751408
2004 The hyphal and yeast forms of Candida albicans bind the complement regulator C4b-binding protein. Infection and immunity 86 15501796
2017 Borrelia burgdorferi outer surface protein C (OspC) binds complement component C4b and confers bloodstream survival. Cellular microbiology 85 28873507
2012 Effect of early syphilis infection on plasma viral load and CD4 cell count in human immunodeficiency virus-infected men: results from the FHDH-ANRS CO4 cohort. Archives of internal medicine 82 22826097
1991 The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera. The Journal of experimental medicine 79 1708809
2012 Enolase of Streptococcus pneumoniae binds human complement inhibitor C4b-binding protein and contributes to complement evasion. Journal of immunology (Baltimore, Md. : 1950) 78 22925928
1987 The superfamily of C3b/C4b-binding proteins. Federation proceedings 78 2952524
1990 Null alleles of human complement C4. Evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus. The Journal of experimental medicine 76 2295875
2005 Human C4b-binding protein selectively interacts with Neisseria gonorrhoeae and results in species-specific infection. Proceedings of the National Academy of Sciences of the United States of America 71 16275906
2004 The C4b-binding protein-protein S complex inhibits the phagocytosis of apoptotic cells. The Journal of biological chemistry 69 15096498
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