Human C4-binding protein. Association with immune complexes in vitro and in vivo.

Scharfstein, Júlio; Correa, E B; Gallo, Gloria; Nussenzweig, Victor

doi:10.1172/jci109320

Cited by 37 publications

(27 citation statements)

References 16 publications

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“…We have previously localized the binding site for C4b to CCP1-3 (20), whereas binding of C3b in addition requires CCP4 (i.e., CCP1-4) (18). C4BP interacts not only with C4b (21) and C3b (18) but also with anticoagulant protein S (22), serum amyloid P component (23), heparin (24), DNA (25), and a number of bacterial proteins (26).…”

Section: A Typical Hemolytic Uraemic Syndrome (Ahus)mentioning

confidence: 99%

A Novel Non-Synonymous Polymorphism (p.Arg240His) in C4b-Binding Protein Is Associated with Atypical Hemolytic Uremic Syndrome and Leads to Impaired Alternative Pathway Cofactor Activity

Blom

Bergström

Edey

et al. 2008

The Journal of Immunology

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Atypical hemolytic uremic syndrome (aHUS) is a disorder characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations, polymorphisms, and copy number variation in complement factors and inhibitors are associated with aHUS. In this study, we report the first functional non-synonymous polymorphism in the complement inhibitor C4b-binding protein (C4BP) α-chain (c.719G>A; p.Arg240His), which is associated with aHUS. This heterozygous change was found in 6/166 aHUS patients compared with 5/542 normal (χ2 = 6.021; p = 0.014), which was replicated in a second cohort of aHUS patients in which we found 5/170 carriers. The polymorphism does not decrease expression efficiency of C4BP. p.Arg240His is equally efficient as the wild type in binding and supporting degradation of C4BP but its ability to bind C3b and act as cofactor to its degradation both in fluid phase and on surfaces is impaired. This observation supports the hypothesis that dysregulation of the alternative pathway of complement is pivotal for aHUS. Three of the patients carry also mutations in membrane cofactor protein and factor H strengthening the hypothesis that individuals may carry multiple susceptibility factors with an additive effect on the risk of developing aHUS.

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Section: A Typical Hemolytic Uraemic Syndrome (Ahus)mentioning

confidence: 99%

A Novel Non-Synonymous Polymorphism (p.Arg240His) in C4b-Binding Protein Is Associated with Atypical Hemolytic Uremic Syndrome and Leads to Impaired Alternative Pathway Cofactor Activity

Blom

Bergström

Edey

et al. 2008

The Journal of Immunology

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“…C4b-binding protein (C4bp) is a regulator of the classical complement pathway (1)(2)(3)(4). It is required as cofactor for the degradation of fluid phase C4b by the enzyme factor I (C3b inactivator) (1)(2)(3)(4).…”

mentioning

confidence: 99%

“…It is required as cofactor for the degradation of fluid phase C4b by the enzyme factor I (C3b inactivator) (1)(2)(3)(4). It accelerates the decay of the C3 convertase of the classical pathway by dissociating C2a from the C4b,2a complex (3).…”

mentioning

confidence: 99%

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Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b.

Dahlbäck¹,

Smith²,

Müller‐Eberhard³

1983

Proc. Natl. Acad. Sci. U.S.A.

207

128

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C4b-binding protein (C4bp) participates in the regulation of the C3 convertase of the classical pathway of complement. By binding to C4b, which is one of the structural subunits of this enzyme, C4bp accelerates the decay-dissociation of the enzyme and renders C4b susceptible to degradation by factor I (C3b inactivator). C4bp is a high molecular weight plasma protein (Mr = 570,000) composed of apparently identical subunits (Mr = 70,000) linked by disulfide bonds. In plasma and in purified form C4bp also forms a bimolecular complex (Kd = 0.9 x 10-7 M) with protein S, a recently identified vitamin K-dependent plasma protein. The binding sites on C4bp for protein S and C4b are distinct and noncompetitive and protein S does not influence the function of C4bp as a regulator of the C3 convertase. C4bp, C4b, and protein S were visualized by electron microscopy by negative staining. C4bp was found to have an unusual spider-like structure.

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“…Complement component C4b-binding protein (C4BP) regulates the classical pathway of the complement system by accelerating the decay of the complement component C3 convertase (C4bC2a) and by acting as a cofactor to the serine protease factor I in the degradation of C4b (1)(2)(3)(4)(5). Approximately 50% of C4BP in plasma is noncovalently complexed with the anticoagulant vitamin K-dependent protein S (6).…”

mentioning

confidence: 99%

Cloning of cDNA coding for the beta chain of human complement component C4b-binding protein: sequence homology with the alpha chain.

Hillarp

Dahlbäck

1990

Proc. Natl. Acad. Sci. U.S.A.

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The major form of complement component C4b-binding protein, a regulator of the complement system, is composed of seven identical 70-kDa a chains, each containing a binding site for the complement protein C4b. We recently showed that C4b-binding protein also contains a uhique 45-kDa (3 chain. It is disulfide-linked to the central core and contains a binding site for the vitamin K-dependent protein S. We have now isolated and characterized full-length cDNA clones for the .8 chain. In addition, 57% of the structure was determined by protein sequencing of tryptic and chymiotryptic peptides. Two clones, A8 and C1, isolated from different libi-aries were sequenced. Except for a deleted triplet encoding Ala-3 in clone A8, the two clones were identical and coded for a leader sequence of 17 amino acids and a mature protein of 235 amino acids (including Ala-3). By N-terminal amino acid sequencing, the Ala-3 heterogeneity was confirmed and a third fl-chain species starting at Glu-4 was identified. The (3 chain contains five potential N-linked glycosylation sites, and endoglycosidase digestion suggested that the ,( chain contained multiple complex carbohydrate side chains. Northern blot analysis of human liver mRNA, using the fl-chain cDNA as the probe, demonstrated a major mRNA species of approximately 1.0 kilobase. From the N terminus, the (3 chain contains three tandem repeat units (60 amino acids long) that are homologous to those present in the a chain. The C-terminal region, which was unrelated to the tandem repeats, demonstrated sequence similarity with the corresponding region of the a chain. In both a and ,B chains these regions contain two cysteine residues that probably form the interchain disulfide bridges.

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Human C4-binding protein. Association with immune complexes in vitro and in vivo.

Cited by 37 publications

References 16 publications

A Novel Non-Synonymous Polymorphism (p.Arg240His) in C4b-Binding Protein Is Associated with Atypical Hemolytic Uremic Syndrome and Leads to Impaired Alternative Pathway Cofactor Activity

A Novel Non-Synonymous Polymorphism (p.Arg240His) in C4b-Binding Protein Is Associated with Atypical Hemolytic Uremic Syndrome and Leads to Impaired Alternative Pathway Cofactor Activity

Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b.

Cloning of cDNA coding for the beta chain of human complement component C4b-binding protein: sequence homology with the alpha chain.

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