Affinage

C4B

Complement C4-B · UniProt P0C0L5

Length
1744 aa
Mass
192.8 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C4B is one isotype of complement component C4, a non-enzymatic protein of the classical and lectin activation pathways that, once cleaved, deposits its C4b fragment covalently onto activating surfaces to nucleate the C3 convertase (PMID:11367523, PMID:2937839). The functional distinction between the C4B and C4A isotypes is dictated by a single isotypic residue: H1106 in C4B catalyzes transacylation of the thioester carbonyl to form ester bonds preferentially with carbohydrate antigens, whereas D1106 in C4A favors amide bonds with protein antigens, accounting for their divergent binding preferences and the lower CR1-enhancing/immune-complex activity of C4B (PMID:11367523, PMID:2138067, PMID:3264881). C1-mediated deposition is geometrically constrained, placing C4b near the Fab regions of bound IgG3 because of the elevated height of the C1-IgG3 complex above the target surface (PMID:37419978). Surface-bound C4b is a true effector that can itself trigger the alternative pathway, an activity suppressed by C4-binding protein (C4BP) (PMID:2937839). Once deposited, C4b is controlled by regulators: the membrane cofactor MCP/CD46 is the primary cofactor for factor I-mediated cleavage of cell-bound C4b (PMID:3950547, PMID:12055245), while fluid-phase C4BP serves as a cofactor for factor I cleavage of soluble C4b and accelerates decay of the surface convertase (PMID:458376, PMID:19660812). Beyond (PMID:11367523), the C4B isotype itself is largely defined by these covalent-attachment and convertase properties; the extensive accompanying corpus characterizes its principal regulator C4BP and that protein's links to coagulation, apoptotic-cell handling, and pathogen immune evasion rather than C4B-specific mechanism.

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1979 High

    Established that a dedicated plasma regulator (C4BP) controls C4b by acting as a factor I cofactor in solution, defining a control point distinct from the C3b-directed regulator factor H.

    Evidence Cofactor assays with purified C3b inactivator and hemolytic erythrocyte intermediates, comparing C4BP and factor H

    PMID:458376

    Open questions at the time
    • Did not resolve which cofactor handles cell-bound C4b
    • No domain-level mapping of the C4b site
  2. 1983 High

    Defined the architecture of C4BP and discovered it carries the anticoagulant protein S, linking complement regulation to coagulation through a distinct subunit.

    Evidence Purification, EM, ultracentrifugation and equilibrium binding of C4BP, protein S and C4b

    PMID:6222381 PMID:6223625

    Open questions at the time
    • Identity of the protein S-binding subunit not yet established
    • C4b and protein S sites localized topologically but not at residue level
  3. 1986 High

    Showed C4b is also regulated at cell surfaces by membrane cofactor protein (MCP/CD46), and that C4BP binding to protein S abolishes protein S anticoagulant cofactor function — coupling the two systems mechanistically.

    Evidence Purified-component cofactor assays for MCP; factor Va degradation assays with C4BP-bound protein S

    PMID:2943733 PMID:3950547

    Open questions at the time
    • Physiological balance between MCP and C4BP for C4b regulation unresolved
    • In vivo consequences of protein S sequestration not yet tested
  4. 1988 High

    Mapped the protein S-binding determinant to a discrete ~45-kDa central-core subunit (later the beta-chain) and a C-terminal peptide, distinguishing C4BP forms that do and do not bind protein S.

    Evidence Guanidine gel filtration, chymotrypsin protection, peptide sequencing and monoclonal antibody blocking

    PMID:2460456 PMID:2956264 PMID:2970465

    Open questions at the time
    • Reciprocal protein S residues not yet identified
    • Functional purpose of C4BP-low isoform unclear
  5. 1992 High

    Localized the reciprocal binding determinants on protein S (SHBG-like region, G-type domains, residues 453-460/605-614) and on the C4BP beta-chain CCP1, building a residue-level picture of the protein S-C4BP interface.

    Evidence Recombinant chimera and alanine-scanning mutagenesis of protein S and C4BP; SPR, peptide competition, phage display and antibody mapping

    PMID:10583388 PMID:11847209 PMID:12440957 PMID:1533219 PMID:2530213 PMID:8300581

    Open questions at the time
    • Co-crystal structure of the complex not determined
    • Relative contribution of each contact to in vivo free protein S levels not quantified
  6. 1991 High

    Demonstrated in vivo that C4BP sequestration of free protein S has physiological consequences, worsening coagulopathy during bacterial challenge — a rescue with excess protein S confirmed the mechanism.

    Evidence Baboon E. coli sepsis model with infusion of purified C4BP and protein S and epistasis/rescue design

    PMID:1829967

    Open questions at the time
    • Human relevance of the effect not directly demonstrated
    • Quantitative threshold of free protein S depletion not defined
  7. 1997 High

    Mapped the C4b-binding and factor I-cofactor function of C4BP to alpha-chain CCP1-3, showing loss of C4b binding eliminates all classical-pathway inhibitory activity.

    Evidence Recombinant chimeric C4BP proteins, monoclonal antibody epitope mapping, EM and functional cofactor/inhibition assays

    PMID:12440957 PMID:9163340

    Open questions at the time
    • Precise stoichiometry of CCP-C4b contacts not resolved at this stage
    • Lectin- vs classical-pathway C4b discrimination not yet addressed
  8. 2001 High

    Defined the molecular basis of C4A/C4B isotype divergence, identifying H1106 in C4B as the transacylation catalyst directing ester-bond formation with carbohydrate antigens versus D1106 amide bonds in C4A.

    Evidence Site-directed mutagenesis at isotypic residues with covalent binding and complement receptor assays

    PMID:11367523 PMID:2138067 PMID:3264881

    Open questions at the time
    • Structural basis of the H1106-catalyzed transacylation not directly visualized
    • Consequences of isotype choice for in vivo target selection not quantified
  9. 2002 High

    Resolved which cofactor cleaves cell-bound versus fluid-phase C4b, establishing MCP/CD46 as the primary surface cofactor and fluid-phase C4BP for soluble C4b.

    Evidence MCP-transfected CHO cells with FACS/Western fragment analysis and function-blocking antibodies

    PMID:12055245

    Open questions at the time
    • Relative contribution under physiological conditions not quantified
    • Cooperativity between MCP and C4BP not examined
  10. 2003 High

    Extended C4BP beyond complement regulation, showing its alpha-chain engages CD40 on B cells to drive proliferation and IgE class switching, and a separate role protecting dead cells from complement.

    Evidence Direct CD40 binding, B cell activation/isotype assays with CD40/NEMO-deficient patient controls; necrotic/apoptotic cell binding via DNA and phosphatidylserine with mutagenesis and phagocytosis assays

    PMID:12818164 PMID:15096498 PMID:15967823 PMID:18556068

    Open questions at the time
    • Physiological significance of C4BP-CD40 signaling in vivo unclear
    • Whether C4B isotype deposition is altered on these protected surfaces not addressed
  11. 2009 Medium

    Showed C4BP discriminates lectin- from classical-pathway-deposited C4b with higher affinity and can engage all seven alpha-chains simultaneously at high C4b density, defining the avidity logic of convertase regulation.

    Evidence Surface convertase decay assays on zymosan/mannan surfaces with SPR and varied C4b density

    PMID:19660812

    Open questions at the time
    • Single lab
    • Structural basis for pathway discrimination not determined
  12. 2016 High

    Provided structural understanding of how C4BP alpha-chain CCP1-3 is exploited by pathogens and recruited by host molecules, acting as a 'reading head' for diverse ligands.

    Evidence Crystal structures of CCP1-3 with four M proteins; direct binding/cofactor assays for flavivirus NS1, PTX3, influenza A proteins

    PMID:21642539 PMID:21915248 PMID:27595425 PMID:33488586

    Open questions at the time
    • Whether C4B-specific C4b deposition influences these recruitments not tested
    • In vivo contribution to pathogen immune evasion not quantified
  13. 2023 High

    Revealed that C4b deposition by C1 is geometrically constrained, landing near IgG3 Fab regions because of the height of the C1-IgG3 complex above the surface.

    Evidence Cryo-EM of IgG3 and complement complexes with mass spectrometry of C4b attachment sites

    PMID:37419978

    Open questions at the time
    • Whether C4A vs C4B isotype affects deposition geometry not examined
    • Generalization to other IgG subclasses not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A direct structural model of the H1106-catalyzed transacylation reaction and of how C4B isotype choice shapes target selection in vivo remains unresolved.
  • No crystal/cryo-EM structure of activated C4B thioester chemistry
  • C4B-specific (versus C4BP-centric) functional corpus is limited

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-109582 Hemostasis 2
Partners
C1C4BPC4BP (FACTOR I COFACTOR)FACTOR IMCP/CD46PROTEIN S
Complex memberships
C3 convertase (C4b2a)C4BP-protein S complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 Membrane cofactor protein (MCP/gp45-70) functions as a cofactor for factor I-mediated cleavage of C4b (and C3b), being ~50-fold more efficient than factor H for the first cleavage of C3b but less efficient than C4BP for C4b cleavage; it has no decay-accelerating activity. Sequential four-column purification including C3(H2O) affinity chromatography; functional cofactor assays with purified components The Journal of experimental medicine High 3950547
1983 C4b-binding protein (C4BP) purified from human plasma has Mr ~570,000, is composed of ~8 subunits (~70 kDa each), and forms a high-affinity (Kd ~0.9×10⁻⁷ M) 1:1 bimolecular complex with vitamin K-dependent protein S; one form of C4BP (higher-MW) binds protein S while the lower-MW form does not. Barium citrate adsorption, multi-step chromatographic purification, ultracentrifugation, SDS-PAGE, agarose-gel electrophoresis, equilibrium binding studies with purified components The Biochemical journal High 6223625
1983 Electron microscopy revealed C4BP has a spider-like structure with seven thin (~30 Å), elongated (~330 Å) flexible subunits linked to a small central body; C4b binds at the peripheral ends of the elongated subunits (seven C4b-binding sites per molecule), and protein S binds through one of its globular domains to a short, distinct eighth subunit of C4BP; the binding sites for protein S and C4b are distinct and noncompetitive. Negative-stain electron microscopy of purified C4BP, protein S, and C4b; binding assays with purified components Proceedings of the National Academy of Sciences of the United States of America High 6222381
1986 C4BP inhibits the protein Ca (activated protein C) cofactor activity of protein S; binding of protein S (from human or bovine origin) to human C4BP results in complete loss of protein S's ability to act as a cofactor for protein Ca-mediated degradation of factor Va. Plasma and purified component systems with human and bovine proteins; factor Va degradation assays; agarose-gel electrophoresis to monitor complex formation The Journal of biological chemistry High 2943733
1979 C4BP serves as a cofactor for C3b inactivator (factor I)-mediated cleavage of C4b in solution; it also has weak cofactor activity for fluid-phase C3b cleavage but has no activity on cell-bound C3b, distinguishing it functionally from factor H (beta1H). Ion-exchange chromatography separation of C4BP forms; functional cofactor assays with purified C3b inactivator; hemolytic assays with erythrocyte intermediates The Journal of experimental medicine High 458376
1988 C4BP contains a novel ~45-kDa subunit (distinct from the seven ~70-kDa subunits) located in the disulfide-linked central core; this subunit is essential for protein S binding, as chymotrypsin cleavage of this subunit abolishes protein S binding, and the presence of protein S protects this subunit from proteolytic degradation. Gel filtration in 6M guanidine HCl; SDS-PAGE; amino-terminal sequencing; chymotrypsin digestion protection assays; stoichiometry determination The Journal of biological chemistry High 2970465
1983 In the presence of C4BP-protein S complex, the degradation of C4b by factor I is not affected by protein S; the binding sites on C4BP for protein S and C4b are independent, and protein S neither participates in nor alters the C4BP–C4b interaction. SDS-PAGE monitoring of fluid-phase C4b degradation; haemolytic assay for surface-bound C4b; highly purified components The Biochemical journal High 6223626
1987 The protein S-binding site on C4BP is localized to the 160-kDa central core fragment (not the 48-kDa peripheral tentacle fragments); the binding requires proper disulfide bond arrangement, and the isolated core retains the same affinity for protein S as intact C4BP. Chymotrypsin digestion of C4BP; gel filtration isolation of fragments; immunoblotting; direct binding assay; disulfide bond reduction experiments The Journal of biological chemistry High 2956264
1988 The protein S-binding site on C4BP maps to the C-terminal region of the C4BP subunit (residues ~Ser447–Tyr467 of the C4BP subunit); a monoclonal antibody (MFbp16) against this region blocks protein S binding; C4BP-low lacks this site and does not bind protein S. Chymotrypsin digestion; monoclonal antibody affinity chromatography; peptide isolation and sequencing; competitive binding assays with purified C4BP The Journal of biological chemistry High 2460456
1989 The C-terminal region of protein S (sequence GVQLDLDEAI, residues 605-614) is involved in the interaction with C4BP; a synthetic peptide with this sequence inhibits protein S binding to C4BP, enhances free protein S levels in plasma, and C4BP binds directly to this peptide. Synthetic peptide inhibition assays; plasma clotting assays; direct C4BP binding to immobilized peptide The Journal of biological chemistry Medium 2530213
1990 Serum amyloid P component (SAP) forms a high-affinity calcium-dependent complex with C4BP; this SAP-C4BP complex coexists with protein S and C4b binding independently, and the entire assembly (C4BP, SAP, protein S, C4b) can associate with phospholipid membranes via the protein S component. Light scattering, gel filtration, sucrose density gradient ultracentrifugation; detection in normal serum; phospholipid vesicle binding assays The Journal of biological chemistry Medium 2147688
1990 Protein S bound to phospholipid membranes in a calcium-dependent manner, and C4BP subsequently associated with membrane-bound protein S with very high affinity (KD ≤10⁻¹⁰ M in presence of calcium); C4BP bound to protein S on the phospholipid surface retained ability to bind complement C4b, localizing complement regulatory activity to negatively charged phospholipid membranes. Light scattering kinetics; phospholipid vesicle binding assays; association/dissociation rate measurements with purified components The Journal of biological chemistry High 2144523
1991 C4BP, by sequestering protein S, exacerbates the coagulopathic response to sublethal E. coli challenge in baboons; co-infusion of C4BP with protein S (to saturate C4BP binding sites) prevented this effect, demonstrating that the mechanism operates through neutralization of free protein S anticoagulant activity. In vivo baboon model; infusion of purified C4BP, protein S, and E. coli; measurement of fibrinogen consumption, organ damage, TNF, and coagulation parameters Blood High 1829967
1992 The protein S-C4BP interaction involves the SHBG-like region of protein S; the sequence Gly605-Ile614 is important but not solely responsible for high-affinity binding; bovine protein S and a human protein S analog with bovine sequence Gly597-Trp629 bound human C4BP with the same affinity as human protein S. Site-specific mutagenesis of recombinant protein S expressed in HEK293 cells; solution-phase C4BP binding assays; thrombin cleavage, APC cofactor assays; gamma-carboxyglutamic acid content analysis The Journal of biological chemistry High 1533219
1994 C4BP beta-chain residues 31-45 (VCIKGYHLVGKKTLF) provide a binding site for protein S; the sequence YxLVG within this region is crucial; peptide beta(31-45) inhibits APC cofactor activity of protein S in factor Xa-stage coagulation assays, and protein S binds directly to the immobilized peptide. Synthetic overlapping pentadecapeptides covering full beta-chain sequence; inhibition of protein S-C4BP complex formation; direct binding assays; anticoagulant cofactor assays; polyclonal antibody inhibition studies The Journal of biological chemistry High 8300581
1993 Murine C4BP SCR1-3 are necessary and sufficient for binding to C4b; constructs with only SCR1-2 or SCR2-6 do not bind C4b, indicating an absolute requirement for SCR1; steric effects near the cell surface can impede binding. Cell-surface fusion protein constructs of mC4BP SCRs fused to CR2 transmembrane domain; erythrocyte rosette assays with C4b-bearing EAC14 cells; inhibition with excess C4 Journal of immunology (Baltimore, Md. : 1950) High 8450212
1997 The amino-terminal CCP module (CCP1) of the C4BP alpha-chain is crucial for C4b binding and factor I-cofactor activity; chimeric proteins with CCP1 or CCP1-2 replaced by corresponding CCPs from the beta-chain completely lose C4b binding; monoclonal antibodies to CCP1-2 of the alpha-chain block C4b binding and factor I-cofactor activity. Chimeric recombinant C4BP proteins; monoclonal antibody generation and mapping with chimeric proteins; C4b binding assays; factor I cofactor activity assay; electron microscopy of antibody-C4BP complexes The Biochemical journal High 9163340
1998 Molecular modeling of C4BP alpha-chain CCPs 1-8 combined with heparin binding experiments and monoclonal antibody studies identified a patch of positively charged residues at the interface between CCP1 and CCP2 as important for interactions with C4b, bacterial Arp/Sir proteins, and heparin. Homology-based computer modeling; heparin binding experiments; monoclonal antibody inhibition studies; EM data integration Proteins Low 9626699
2002 The C4b binding site on C4BP requires CCP1-3 of the alpha-chain, and the interaction is ionic in nature mediated by a cluster of positively charged amino acids at the interface of CCP1 and CCP2; heparin binding also requires CCPs1-3 with CCP2 most important and overlaps with the C4b binding site; the protein S-binding site is conveyed by hydrophobic amino acids on CCP1 of the beta-chain. Homology-based modeling combined with mutagenesis of recombinant proteins; binding assays for C4b, heparin, and protein S; complement inhibition assays Biochemical Society transactions Medium 12440957
2002 C4b binding and factor I cofactor activity of C4BP are lost upon replacement of alpha-chain CCP1-3 with corresponding CCPs from the beta-chain; this also confirms that loss of C4b binding results in complete loss of all inhibitory functions of C4BP in the classical complement pathway. Recombinant chimeric C4BP proteins; C4b binding assays; factor I cofactor activity assays; complement pathway inhibition assays Biochemical Society transactions Medium 12440957
2002 The C4BP alpha-chain CCP1 of the beta-chain (not alpha-chain) conveys protein S binding via a cluster of surface-exposed hydrophobic amino acids; this is distinct from the C4b/heparin binding sites on the alpha-chain. Mutagenesis of recombinant C4BP beta-chain CCP1; surface plasmon resonance and binding assays for protein S Biochemical Society transactions Medium 12440957
2003 The alpha-chain of C4BP binds directly to CD40 on human B cells at a site differing from that used by CD40 ligand; this interaction induces B cell proliferation, upregulation of CD54 and CD86, and IL-4-dependent IgE isotype switching, but not in B cells from CD40- or IKKgamma/NEMO-deficient patients; C4BP colocalizes with B cells in germinal centers. Direct binding assay of C4BP alpha-chain to CD40; B cell proliferation and activation assays; IgE isotype switching assays; patient B cells with CD40/IKKgamma deficiency as genetic controls; immunohistochemistry of tonsil sections Immunity High 12818164
2005 C4BP binds strongly to necrotic cells (but not viable cells) via two mechanisms: protein S component of the C4BP-PS complex interacts with phosphatidylserine, and C4BP itself binds DNA via a patch of positively charged amino acids mainly on CCP2 of the alpha-chain (affinity constant ~190 nM); C4BP-PS on necrotic cells inhibits complement activation and limits DNA release. Direct binding assays with necrotic and apoptotic cells; SPR for DNA binding; mutagenesis of C4BP alpha-chain CCPs; complement activation assays; immunohistochemistry of atherosclerotic plaques and cancers The Journal of experimental medicine High 15967823
2004 The C4BP-protein S complex strongly inhibits phagocytosis of apoptotic cells by primary human macrophages and THP-1 cells, whereas free protein S enhances phagocytosis; this inhibitory effect of C4BP-PS is blocked by anti-Gla domain antibodies against protein S. Phagocytosis assays with BL-41 and Jurkat apoptotic cells; primary human macrophages and THP-1 cells; purified C4BP-PS complex; protein S-depleted serum reconstitution; monoclonal antibody blocking The Journal of biological chemistry High 15096498
1999 Both G-type (globular) domains of the SHBG-like region of protein S contribute to C4BP binding; chimeras with only G1 or only G2 from protein S both bind C4BP, but with lower affinity than wild-type; G1-containing chimera binds more efficiently than G2-containing chimera; the whole Gas6 SHBG-like region bound C4BP very weakly. Recombinant protein S chimeras with Gas6 substitutions; surface plasmon resonance; microtiter plate binding assays; calcium dependency studies European journal of biochemistry High 10583388
2002 Protein S residues 453-460 form part of the C4BP binding site; the Y456A mutation reduces C4BP binding ~10-fold; introduction of an N-glycosylation site at Y456N/N458T further reduces binding; a monoclonal antibody (HPSf) specific for free protein S reacts poorly with Y456A variant, and antibody HPS34 that partially inhibits the protein S-C4BP interaction maps its epitope to residues 451-460. Alanine scanning mutagenesis of recombinant protein S residues 447-460; SPR binding assays; peptide inhibition assays; phage display; monoclonal antibody epitope mapping The Journal of biological chemistry High 11847209
2001 C4B protein (and C4A) binds covalently to immune complexes and complement receptors; site-directed mutagenesis revealed that residue D1106 of C4A is responsible for effective amide bond formation with protein antigens, while H1106 of C4B catalyzes transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens, explaining the functional differences between C4A and C4B isotypes. Site-directed mutagenesis of C4A/C4B isotypic residues (positions 1101, 1102, 1105, 1106); covalent binding assays to immune aggregates and carbohydrate antigens; complement receptor binding assays International immunopharmacology High 11367523
1990 C4A is markedly more effective than C4B at enhancing binding of immune complexes to CR1 on erythrocytes; C4A is only modestly more effective than C4B at inhibiting immunoprecipitation; the major functional difference between C4A and C4B is at the level of CR1 binding. CR1 binding assays with preformed and nascent immune complexes; immune complex precipitation inhibition assays; purified C4A and C4B Clinical and experimental immunology Medium 2138067
1988 C4A binds 3-4 times more IgG than C4B1 in fluid phase; C4A3 binds via predominantly amide linkage, whereas C4B1 binds via either amide or acyl ester bonds; C4A3 also has higher binding efficiency for IgM, IgA, IgG2a, F(ab')2, and BSA. Fluid-phase binding assay with purified C4 and C1s; SDS-PAGE analysis of covalent bonds; use of C4A-only serum to confirm bond types Molecular immunology Medium 3264881
1986 C4b molecules deposited on erythrocyte surfaces via the classical pathway can activate the alternative complement pathway; this activation is suppressed by anti-C4 antibody or C4-binding protein, establishing C4b as a surface-bound activator of the alternative pathway. Erythrocyte intermediate cell model; Mg-EGTA-GVB complement activation assays; C2-deficient human serum controls; anti-C4 antibody and C4BP inhibition experiments Journal of immunology (Baltimore, Md. : 1950) Medium 2937839
2009 C4BP regulates the lectin pathway C3/C5 convertase assembled on surfaces 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 engage C4b simultaneously (up to 8.23 C4b per C4BP). Surface-bound C3/C5 convertase assembly and decay assays on zymosan and mannan-coated erythrocytes; SPR binding studies; C4b density variation experiments Molecular immunology Medium 19660812
2003 Zinc at micromolar concentrations increases the cofactor activity of C4BP toward C4b and C3b, while zinc at ≥2 mM abolishes this activity; zinc binds directly to C4b and C3b (not to C4BP or factor I), and low zinc concentrations increase affinity between C4b/C3b and cofactor proteins as measured by SPR; high zinc causes aggregation of C4b/C3b. Factor I cofactor activity assays; ⁶⁵Zn overlay of nitrocellulose-immobilized proteins; fluorescent chelator Zn²⁺ binding constant determination; surface plasmon resonance Archives of biochemistry and biophysics Medium 14522582
1995 The C4BP-protein S complex synergistically inhibits intrinsic factor X activation; C4BP alone has no effect, but binding to protein S potentiates inhibition from ~50% to ~90%; C4BP (via its alpha-chain, not beta-chain) binds directly to factor VIII and thrombin-activated factor VIII, and this interaction mediates the potentiation of protein S inhibitory effects on the factor X activation complex. Factor X activation assays with purified components; C4BP binding assays to immobilized factor VIII; monoclonal antibody blocking studies with anti-alpha and anti-beta chain antibodies; SPR or competitive binding Blood Medium 7670108
2011 Flavivirus (dengue, West Nile, yellow fever) NS1 protein binds directly to C4BP, with the NS1 interaction site on C4BP partially overlapping the C4b binding sites; NS1 recruits C4BP to inactivate C4b in solution and on plasma membranes, thus limiting complement activation. Direct binding assays; C4b inactivation assays with soluble and membrane-bound C4b; mapping studies with C4BP/NS1 interaction Journal of immunology (Baltimore, Md. : 1950) Medium 21642539
2011 PTX3 binds C4BP at a site within CCP1-3 of the C4BP alpha-chain; C4BP bound to PTX3 on surfaces retains full complement regulatory activity; C1q and L-ficolin compete with C4BP for PTX3 binding; PTX3 recruits functionally active C4BP to extracellular matrices and enhances C4BP binding to late apoptotic cells, increasing C4b inactivation and reducing C5b-9 deposition. Direct binding assays; complement activation assays on ECM and apoptotic cells; competition assays with C1q and L-ficolin; C4BP cofactor activity assays PloS one Medium 21915248
2016 C4BP CCP1-3 of the alpha-chain forms a 'reading head' that recognizes conserved sequence patterns within the hypervariable regions of Group A Streptococcus M proteins; crystal structures of four sequence-diverse M protein-C4BP complexes revealed the structural basis for broad M-type cross-reactivity. Crystal structure determination of C4BP CCP1-3 in complex with four different M proteins Nature microbiology High 27595425
2023 C1 deposits C4b directly onto specific IgG3 residues proximal to the Fab domains (not Fc); structural analysis shows this localization is caused by the elevated height of the C1-IgG3 complex above the target surface, as revealed by cryo-EM structures. CryoEM structure determination of IgG3 alone and in complex with complement components; mass spectrometry to identify specific C4b deposition sites on IgG3 Nature communications High 37419978
2008 C4BP directly binds amyloid-beta (Aβ1-42) peptide via the C4BP alpha-chain, and binds apoptotic and necrotic (but not viable) brain cells including astrocytes, neurons and oligodendrocytes; C4BP binding to dead brain cells and Aβ limits complement activation on these substrates in vitro. Direct binding assays with Aβ1-42 and brain cell types; complement activation assays; immunohistochemistry of AD brain sections Molecular immunology Medium 18556068
2021 C4BP binds influenza A virus (IAV) envelope proteins hemagglutinin, neuraminidase, and matrix protein 1 via multiple sites in CCP1-2, 4-5, and 7-8 of the alpha-chain; C4BP suppresses H1N1 infection and restricts H1N1 viral entry into A549 cells in a complement-independent manner, while promoting H3N2 infection; C4BP downregulates pro-inflammatory IFN-α, IL-12, and NFκB mRNA for H1N1 but upregulates them for H3N2. Binding assays with IAV subtypes and individual viral proteins; pseudotyped viral particle entry assays; infection assays in A549 cells; qPCR for cytokine mRNA Frontiers in immunology Medium 33488586
1993 The human C4BP beta-chain gene spans >10 kb, contains exons encoding three SCRs and a C-terminal non-repeat region, and produces two distinct mRNA classes (A19 and A12) with different 5'-untranslated regions arising from different transcription start sites; the mouse C4BPB gene is a single-copy pseudogene due to two in-phase stop codons, explaining why mice lack a functional C4BP beta-chain and hence cannot form the protein S-C4BP complex. Genomic DNA isolation and sequencing; Northern blotting; primer extension; S1 nuclease protection assays; genomic mapping in multiple mouse strains The Journal of biological chemistry High 7959726 8325877
2002 MCP (CD46) is the primary cofactor mediating cleavage of C4b deposited on cells in the classical pathway (not fluid-phase C4BP); C4b on MCP(+) cells is progressively cleaved to C4d and C4c within an hour, with no detectable cleavage on MCP(-) cells; factor H is the responsible cofactor for C3b cleavage on cells. FACS and Western blotting of complement fragments on MCP-transfected CHO cells; function-blocking anti-MCP and anti-factor H monoclonal antibodies; Mg²⁺-EGTA alternative pathway activation Journal of immunology (Baltimore, Md. : 1950) High 12055245

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 C-H...pi-interactions in proteins. Journal of molecular biology 453 11243825
1986 Purification and characterization of a membrane protein (gp45-70) that is a cofactor for cleavage of C3b and C4b. The Journal of experimental medicine 387 3950547
1983 Purification of human C4b-binding protein and formation of its complex with vitamin K-dependent protein S. The Biochemical journal 305 6223625
2002 Functional plasticity of CH domains. FEBS letters 273 11911887
1986 Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein. The Journal of biological chemistry 259 2943733
2015 Manganese Catalyzed C-H Halogenation. Accounts of chemical research 233 26042637
1983 Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b. Proceedings of the National Academy of Sciences of the United States of America 228 6222381
2015 Olefinic C-H functionalization through radical alkenylation. Chemical Society reviews 197 25553785
2002 Kinase inhibitors and the case for CH...O hydrogen bonds in protein-ligand binding. Proteins 183 12402365
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
2002 CH...O hydrogen bonds at protein-protein interfaces. The Journal of biological chemistry 150 12119293
1991 C4b-binding protein exacerbates the host response to Escherichia coli. Blood 144 1829967
1988 Novel subunit in C4b-binding protein required for protein S binding. The Journal of biological chemistry 144 2970465
1979 The role of C4-binding protein and beta 1H in proteolysis of C4b and C3b. The Journal of experimental medicine 142 458376
2001 Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4. International immunopharmacology 134 11367523
1991 Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thrombosis and haemostasis 134 1828915
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