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HGNC Approved Gene Symbol: C4BPA
Cytogenetic location: 1q32.2 Genomic coordinates (GRCh38): 1:207,104,233-207,144,972 (from NCBI)
C4b (120820)-binding protein is involved in regulation of the complement system. It is a multimeric protein comprising 7 identical alpha chains, encoded by C4BPA, and a single beta chain, encoded by C4BPB (120831). The alpha and beta chains have molecular masses of 70 and 45 kD, respectively. Both subunits belong to a superfamily of proteins composed predominantly of tandemly arranged short consensus repeats (SCR) of approximately 60 amino acids in length (Aso et al., 1991).
By isoelectric focusing under completely denaturing conditions, Rodriguez de Cordoba et al. (1983, 1984) identified 2 allelic variants of C4BP.
Matsuguchi et al. (1989) showed that proline-rich protein (PRP), a glycoprotein present in chylomicrons, is identical to C4BP.
C4BP of man has been studied by Gigli et al. (1979) and Nagasawa and Stroud (1980). Gigli et al. (1979) showed that C4BP is an essential cofactor for C3b inactivator (CFI; 217030) in the proteolytic cleavage of C4b and, to a lesser extent, of C3b (120700), and functions as the regulator of C3 convertase of the classical pathway. Kaidoh et al. (1981) stated that the C3 convertase of the classical pathway consists of C2 (613927) and C4; that of the alternative pathway of factor B (CFB; 138470) and C3 (120700). Each C3 convertase plays a key role in the amplification process of complement activation.
Brodeur et al. (2003) identified a 23-kD protein that bound CD40 (109535) as C4BP-alpha. Flow cytometric analysis demonstrated binding of C4BP to human B-cell lines expressing CD40, but not to cells from CD40-deficient patients. Competitive binding analysis showed that CD40LG (300386) and C4BP bound distinct sites on CD40. C4BP induced proliferation, upregulation of CD54 (ICAM1; 147840) and CD86 (601020) surface expression, and, together with IL4 (147780), IgE synthesis in normal B cells, but not in B cells from patients with CD40 or IKBKG (300248) deficiencies. Immunohistochemical analysis showed that C4BP colocalized with CD40 on B cells in tonsillar germinal centers. Brodeur et al. (2003) proposed that C4BP is an activating ligand for CD40 and represents an interface between complement and B-cell activation.
Strains of Neisseria gonorrhoeae use their outer membrane porin (Por) molecules to bind C4BP and resist killing by human, but not rodent, rabbit, and nonhuman primate, serum complement. The lack of susceptibility to N. gonorrhoeae infection in nonhuman species prevents the development of an animal model to study the infection in vivo. Ngampasutadol et al. (2005) found that gonococci expressing Por1B, but not Por1A, were resistant to killing by chimpanzee serum. Addition of human C4BP to animal sera rescued N. gonorrhoeae from killing. Nonhuman C4bp did not bind N. gonorrhoeae. Comparative sequence analysis suggested 4 potential residues in human C4BP that may be critical for its interaction with Por1A. Ngampasutadol et al. (2005) concluded that C4BP sequence differences account for the restriction of serum resistance of N. gonorrhoeae to humans and, in some instances, chimpanzees.
Aso et al. (1991) found that the C4BPA gene comprises 12 exons and spans about 40 kb. Each of the 8 SCRs that constitute the N-terminal 491 residues is encoded by a single exon, except for the second, which is encoded by 2 separate exons.
Rodriguez de Cordoba et al. (1984) studied 3 pedigrees informative for segregation of C4BP and C3b receptor (C3BR, or CR1; 120620). Neither C4BP nor C3BR is closely linked to HLA (Rodriguez de Cordoba et al., 1983; Hatch et al., 1984); however, segregation in the 3 kindreds indicated that the 2 loci are closely linked in man. There were 10 informative meioses with no recombinants--maximum lod score = 2.4 at theta 0.0. The cosegregation of 2 common alleles supported close linkage by the principle of linkage disequilibrium. These 2 closely linked genes determine functionally related proteins. Rodriguez de Cordoba et al. (1985) concluded that HF (CFH; 134370), C4BP, C3BR, and C3DR (CR2; 120650) represent a cluster of linked genes encoding complement components regulating the activation of C3. They called the cluster RCA for regulators of complement activation. They showed, furthermore, that the RCA cluster segregates independently of HLA, the C2, CFB, C4 cluster (on 6p), and C3 (on 19p). Using pulsed-field gel electrophoresis, Rey-Campos et al. (1988) showed that the RCA cluster is physically linked and aligned as CR1--CR2--DAF (CD55; 125240)--C4BP in an 800-kb DNA segment. The very tight linkage between CR1 and C4BP revealed by family linkage studies contrasts with the relatively long DNA distance between these genes, suggesting that there may be mechanisms interfering with recombination within the RCA gene cluster. The probe for HF did not hybridize to any of the fragments recognized by the CR1, CR2, DAF, or C4BP probes. Rey-Campos et al. (1988) estimated that the RCA cluster may exceed 1 Mb in length and, given the recombination data, may be as long as 7 Mb. By Southern analysis of hybrid cell DNA, Hing et al. (1988) assigned C4BP and HF to 1q.
Kaidoh et al. (1981) showed that mouse C4bp is polymorphic and is determined by a gene in the major histocompatibility complex. However, Barnum et al. (1989) assigned the mouse gene to chromosome 1.
PSEUDOGENES
Sanchez-Corral et al. (1993) identified a gene, symbolized C4BPAL1 by them, as a member of the human RCA gene cluster that arose from duplication of the C4BPA gene. It is in the same 5-prime to 3-prime orientation found in all RCA genes. C4BPAL1 includes 9 exon-like regions homologous to several exons of the C4BPA gene. Analysis of its sequence suggested that it is currently a pseudogene in humans. However, comparisons between C4BPAL1 and the human and murine C4BPA genes showed sequence conservation which strongly suggested that, for a long period of time, the gene was functional.
Blom et al. (2008) identified an arg240-to-his (R240H) SNP in the C4BPA gene that was associated with atypical hemolytic uremic syndrome (aHUS; 235400). The heterozygous change was found in 6 of 166 patients with aHUS and in 5 of 542 healthy controls. Three of the 6 patients with this SNP carried mutations in other known aHUS susceptibility genes, including MCP (120920) and CFH (134370). The findings were replicated in another sample. Functional expression studies showed that the C4BPA variant had impaired ability to bind C3b and act as a cofactor in its degradation. The findings supported the hypothesis that dysregulation of the alternative complement pathway can lead to aHUS.
Andersson, A., Dahlback, B., Hanson, C., Hillarp, A., Levan, G., Szpirer, J., Szpirer, C. Genes for C4b-binding protein alpha- and beta-chains (C4BPA and C4BPB) are located on chromosome 1, band 1q32, in humans and on chromosome 13 in rats. Somat. Cell Molec. Genet. 16: 493-500, 1990. [PubMed: 2237642] [Full Text: https://doi.org/10.1007/BF01233199]
Aso, T., Okamura, S., Matsuguchi, T., Sakamoto, N., Sata, T., Niho, Y. Genomic organization of the alpha chain of the human C4b-binding protein gene. Biochem. Biophys. Res. Commun. 174: 222-227, 1991. [PubMed: 1989602] [Full Text: https://doi.org/10.1016/0006-291x(91)90509-6]
Barnum, S. R., Kristensen, T., Chaplin, D. D., Seldin, M. F., Tack, B. F. Molecular analysis of the murine C4b-binding protein gene: chromosome assignment and partial gene organization. Biochemistry 28: 8312-8317, 1989. [PubMed: 2574991] [Full Text: https://doi.org/10.1021/bi00447a008]
Blom, A. M., Bergstrom, F., Edey, M., Diaz-Torres, M., Kavanagh, D., Lampe, A., Goodship, J. A., Strain, L., Moghal, N., McHugh, M., Inward, C., Tomson, C., Fremeaux-Bacchi, V., Villoutreix, B. O., Goodship, T. H. J. 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. J. Immun. 180: 6385-6391, 2008. [PubMed: 18424762] [Full Text: https://doi.org/10.4049/jimmunol.180.9.6385]
Brodeur, S. R., Angelini, F., Bacharier, L. B., Blom, A. M., Mizoguchi, E., Fujiwara, H., Plebani, A., Notarangelo, L. D., Dahlback, B., Tsitsikov, E., Geha, R. S. C4b-binding protein (C4BP) activates B cells through the CD40 receptor. Immunity 18: 837-848, 2003. [PubMed: 12818164] [Full Text: https://doi.org/10.1016/s1074-7613(03)00149-3]
Gigli, I., Fujita, T., Nussenzweig, V. Modulation of the classical pathway C3 convertase by plasma proteins C4 binding protein and C3b inactivator. Proc. Nat. Acad. Sci. 76: 6596-6600, 1979. [PubMed: 293746] [Full Text: https://doi.org/10.1073/pnas.76.12.6596]
Hatch, J. A., Atkinson, J. P., Suarez, B. K., Dykman, T. R. Evaluation of linkage of the human C3b/C4b receptor to HLA. J. Immun. 132: 2168-2169, 1984. [PubMed: 6232312]
Hing, S., Day, A. J., Linton, S. J., Ripoche, J., Sim, R. B., Reid, K. B. M., Solomon, E. Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes. Ann. Hum. Genet. 52: 117-122, 1988. [PubMed: 2977721] [Full Text: https://doi.org/10.1111/j.1469-1809.1988.tb01086.x]
Kaidoh, T., Natsuume-Sakai, S., Takahashi, M. Murine binding protein of the fourth component of complement: structural polymorphism and its linkage to the major histocompatibility complex. Proc. Nat. Acad. Sci. 78: 3794-3798, 1981. [PubMed: 6943584] [Full Text: https://doi.org/10.1073/pnas.78.6.3794]
Matsuguchi, T., Okamura, S., Aso, T., Sata, T., Niho, Y. Molecular cloning of the cDNA coding for proline-rich protein (PRP): identity of PRP as C4b-binding protein. Biochem. Biophys. Res. Commun. 165: 138-144, 1989. [PubMed: 2590215] [Full Text: https://doi.org/10.1016/0006-291x(89)91045-0]
Nagasawa, S., Stroud, R. M. Purification and characterization of a macromolecular weight cofactor for C3b-inactivator, C4bC3bINA-cofactor, of human plasma. Molec. Immun. 17: 1365-1372, 1980. [PubMed: 7464836] [Full Text: https://doi.org/10.1016/0161-5890(80)90005-x]
Ngampasutadol, J., Ram, S., Blom, A. M., Jarva, H., Jerse, A. E., Lien, E., Goguen, J., Gulati, S., Rice, P. A. Human C4b-binding protein selectively interacts with Neisseria gonorrhoeae and results in species-specific infection. Proc. Nat. Acad. Sci. 102: 17142-17147, 2005. [PubMed: 16275906] [Full Text: https://doi.org/10.1073/pnas.0506471102]
Rey-Campos, J., Rubinstein, P., Rodriguez de Cordoba, S. A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP. J. Exp. Med. 167: 664-669, 1988. [PubMed: 2450163] [Full Text: https://doi.org/10.1084/jem.167.2.664]
Rodriguez de Cordoba, S., Dykman, T. R., Ginsberg-Fellner, F., Ercilla, G., Aqua, M., Atkinson, J. P., Rubinstein, P. Evidence for linkage between the loci coding for the binding protein for the fourth component of human complement (C4BP) and for the C3b/C4b receptor. Proc. Nat. Acad. Sci. 81: 7890-7892, 1984. [PubMed: 6240062] [Full Text: https://doi.org/10.1073/pnas.81.24.7890]
Rodriguez de Cordoba, S., Ferreira, A., Nussenzweig, V., Rubinstein, P. Genetic polymorphism of human C4-binding protein. J. Immun. 131: 1565-1569, 1983. [PubMed: 6886425]
Rodriguez de Cordoba, S., Lublin, D. M., Rubinstein, P., Atkinson, J. P. Human genes for three complement components that regulate the activation of C3 are tightly linked. J. Exp. Med. 161: 1189-1195, 1985. [PubMed: 3157763] [Full Text: https://doi.org/10.1084/jem.161.5.1189]
Rodriguez de Cordoba, S., Rubinstein, P., Ferreira, A. High resolution isoelectric focusing of immunoprecipitated proteins under denaturing conditions: a simple analytical method applied to the study of complement component polymorphisms. J. Immun. Methods 69: 165-172, 1984. [PubMed: 6232323] [Full Text: https://doi.org/10.1016/0022-1759(84)90314-4]
Sanchez-Corral, P., Pardo-Manuel de Villena, F., Rey-Campos, J., Rodriguez de Cordoba, S. C4BPAL1, a member of the human regulator of complement activation (RCA) gene cluster that resulted from the duplication of the gene coding for the alpha-chain of C4b-binding protein. Genomics 17: 185-193, 1993. [PubMed: 8406448] [Full Text: https://doi.org/10.1006/geno.1993.1300]