Conclusion
Despite the wealth of structural and functional information on C4BP, it is clear that several aspects of C4BP biology and regulation under normal conditions and in the acute-phase response remain unresolved. Studies to identify which interleukin and cytokines regulate C4BP expression (both α-and β-chains) are underway in our laboratory. In addition, upstream cis-acting regulatory sequences need to be characterized to attempt to correlate structural regulatory elements with expression. C4BP is a unique macromolecular protein and the mechanisms involved in controlling intracellular assembly also will be of interest. Finally, the modest increase of C4BP in SLE suggests dysregulation of altered cytokine responses in these individuals. Further studies in this and other autoimmune diseases should aid in understanding our present findings and may help in understanding C4BP gene regulation.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Gigli I, Fukita T, Nussenzweig V: Modulation of the classical pathway C3 convertase by plasma proteins, C4 binding protein and C3b inactivator. Proc Natl Acad Sci USA 1979;76:6596–6600.
Daha MR, Van Es LA: Relative resistance of the F-42-stabilized classical pathway C3 convertase to inactivation by C4-binding protein. J Immunol 1980;125:2051–2054.
Cooper NR: Isolation and analysis of the mechanism of action of an inactivator of C4b in normal human serum. J Exp Med 1975;141:890–903.
Fujita T, Gigli I, Nussenzweig V: Human C4-binding protein. II. Role in proteolysis of C4b by C3 inactivator. J Exp Med 1978;148:1044–1051.
Nagasawa S, Ichihara C, Stroud RM: Cleavage of C4b by C3 inactivator: Production of a nicked form of C4b, C4b′, as an intermediate cleavage product of C4b by C3b inactivator. J Immunol 1980;125:578–582.
Fujita T, Tamura N: Interaction of C4-binding protein with cell-bound C4b: A quantitative analysis of binding and the role of C4-binding protein in proteolysis of cell-bound C4b. J Exp Med 1983; 1239–1251.
Scharfstein J, Ferreira A, Gigli I, Nussenzweig V: Human C4-binding protein. I. Isolation and characterization. J Exp Med 1978;148:207–222.
Ferreira A, Takahashi M, Nussenzweig V: Purification and characterization of a mouse serum protein with specific binding affinity for C4 (Ss protein). J Exp Med 1977;146:1001–1018.
Burge J, Nicholson-Weller A, Austen KF: Isolation of C4-binding protein from guinea pig plasma and demonstration of its function as a control protein of the classical complement pathway C3 convertase. J Immunol 1981;126:232–235.
Kaldoh T, Natsuume-Sakai S, Takahashi M: Murine C4-binding protein: A rapid purification method by affinity chromatography. J Immunol 1981;126:463–467.
Nagasawa S, Stroud RM: Purification and characterization of a macromolecular weight cofactor for C3b-inactivator, C4bC3bINA-cofactor, of human plasma. Mol Immunol 1980;17:1365–1372.
Dahlback B, Muller-Eberhard HJ: Ultrastructure of C4b-binding protein fragments formed by limited proteolysis using chymotrypsin. J Biol Chem 1984;259:11631–11634.
Chung LP, Gagnon J, Reid KBM: Amino acid sequence studies of human C4b-binding protein: N-terminal sequence analysis and alignment of the fragments produced by limited proteolysis with chymotrypsin and the peptides produced by cynanogen bromide treatment. Mol Immunol 1985;22:427–435.
Chung LP, Bentley DR, Reid KBM: Molecular cloning and characterization of the cDNA coding for C4b-binding protein, a regulatory protein of the classical pathway of the human complement system. Biochem J 1985;230:133–141.
Chung LP, Reid KBM: Structural and functional studies on C4b-binding protein, a regulatory component of the human complement system. Biosci Rep 1985;5:855–865.
Nagasawa S, Unno H, Ichihara C, Koyama J, Koide T: Human C4b-binding protein, C4bp: Chymotryptic cleavage and location of the 48 kDa active fragment within C4bp. FEBS Lett 1983; 164:135–138.
Kristensen T, Ogata RT, Chung LP, Reid KBM, Tack BF: cDNA structure of murine C4b-binding protein, a regulatory component of the serum complement system. Biochemistry 1987;26:4668–4674.
Dahlback B, Smith CA, Muller-Eberhard HJ: Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b. Proc Natl Acad Sci USA 1983;80:3461–3465.
Hillarp A, Dahlback B: Novel subunit in C4b-binding protein required for protein S binding. J Biol Chem 1988;263:12759–12764.
Hillarp A, Hessing M, Dahlback B: Protein S binding in relation to the subunit composition of human C4b-binding protein. FEBS Lett 1989;259: 53–56.
Lintin SJ, Lewin AR, Red KBM: Derivation of the sequence of the signal peptide in human C4b-binding protein and interspecies cross-hybridisation of the C4bp cDNA sequence. FEBS Lett 1988;232:328–332.
Perkins SJ, Chung LP, Reid KBM: Unusual ultrastructure of complement component-C4b-binding protein of human complement by synchroton X-ray scattering and hydrodynamic analysis. Biochem J 1986;233:799–807.
Hillarp A, Dahlback B: Cloning of cDNA coding for the β chain of human complement component C4b-binding protein: Sequence homology with the α chain. Proc Natl Acad Sci USA 1990;87: 1183–1187.
Janatova J, Reid KBM, Willis AC: Disulfide bonds are localized within the short consensus repeat units of complement regulatory proteins: C4b-binding protein. Biochemistry 1989;28: 4754–4761.
Reid KBM, Bentley DR, Campbell RD, Chung LP, Sim RB, Kristensen T, Tack BF: Complement system proteins which interact with C3b or C4b: A superfamily of structurally related proteins. Immunol Today 1986;7:230–234.
Kristensen T, D'Eustachio P, Ogata RT, Chung LP, Reid KBM, Tack BF: The superfamily of C3b/C4b-binding proteins. Fed Proc 1987;46: 2463–2469.
Reid KBM, Day AJ: Structure-function relationships of the complement components. Immunol Today 1989;10:177–180.
Oldberg A, Antonsson P, Heinegard D: The partial amino acid sequence of bovine cartilage proteoglycan, deduced from a cDNA clone, contains numerous Ser-Gly sequences arranged in homologous repeats. Biochem J 1987;243:255–259.
Sai S, Tanaka T, Kosher RA, Tanzer ML: Cloning and sequence analysis of a partial cDNA for chicken cartilage proteoglycan core protein. Proc Natl Acad Sci USA 1986;83:5081–5085.
Krusius T, Gehlsen KR, Rusolahti E: A fibroblast chondroitin sulfate proteoglycan core protein contains lectin-like and growth factor-like sequences. J Biol Chem 1987;262:13120–13125.
Kowtal GJ, Moss B: Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins. Nature 1988;335:176–178.
Ziccardi RJ, Dahlback B, Muller-Eberhard HJ: Characterization of the interaction of human C4b-binding protein with physiological ligands. J Biol Chem 1984;259:13674–13679.
Klickstein LB, Wong WW, Smith JA, Weis JH, Wilson JG, Fearon DT: Human C3b/C4b receptor (CRI): Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristic of C3/C4 binding proteins. J Exp Med 1987;165:1095–1112.
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 Natl Acad Sci USA 1981;78:3794–3798.
Barnum SR, Kristensen T, Chaplin DD, Seldin MF, Tack BF: Molecular analysis of the murine C4b-binding protein gene: Chromosome assignment and partial gene organization. Biochemistry 1989;28:8312–317.
Kingsmore FF, Vik DP, Kurtz CB, Leroy P; Tack BF, Weis JH, Seldin MF: Genetic organization of the complement receptor-related genes in the mouse. J Exp Med 1989;169:1479–1484.
Rodriquez de Cordoba S, Rubenstein P: New alleles of C4-binding protein and factor H and further linkage data in the regulator of complement activation (RCA) gene cluster in man. Immunogenetics 1987;25:267–268.
Lintin SJ, Reid KBM: Studies on the structure of the human C4b-binding protein gene. FEBS Lett 1986;204:77–81.
Rey-Campos J, Marshall P, Rubenstein P, Rodriquez de Cordoba S: Structure of human C4BP gene. Comp Inflamm 1989;6:393–394.
Vik DP, Keeny JB, Munoz-Canoves P, Chaplin DD, Tack BF: Structure of the murine complement factor H gene. J Biol Chem 1988;263: 16720–16724.
Wong WW, Cahill JM, Rosen MD, Kennedy CA, Bonaccio ET, Morris MJ, Wilson JG, Klickstein LB, Fearon DT: Structure of the human CR1 gene: Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele. J Exp Med 1989;169:847–863.
Fujiskau A, Harley JB, Frank MB, Gruner BA, Frazier B, Holers VM: Genomic organization and polymorphisms of the human C3d/Epstein Barr virus receptor. J Biol Chem 1989;264:2118–2125.
Post TW, Atkinson JP: The structure and organization of the MCP gene. FASEB J 1989;3:368.
Lublin DM, Post TW, Arce MA, Liszewski MK, Atkinson JP: Structure of human DAF gene. FASEB J 1989;3:801.
Benoist C, O'Hare K, Breathnach R, Chambon P: The ovalbumin gene sequence of putative control regions. Nucl Acids Res 1980;8:127–142.
Berget S: Are U4 small nuclear ribonucleoproteins involved in polyadenylation? Nature 1984;309: 179–182.
Carroll MC, Alicot EM, Katzman PJ, Klickstein LB, Smith JA, Fearon DT: Organization of the genes encoding complement receptors type 1 and 2, decay accelerating factor, and C4-binding protein in the RCA locus on human chromosome 1. J Exp Med 1988;167:1271–1280.
Rey-Campos J, Rubinstein P, Rodriquez 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 1988;167:664–669.
Bora NS, Lublin DM, Kumar BV, Hockett RD, Holers VM, Atkinson JP: Structural gene for human membrane cofactor protein (MCP) of complement maps to within 100 kb of the 3′ end of the C3b/C4b receptor gene. J Exp Med 1989;169: 597–602.
McGill JR, Chirgwin JM, Moore CM, McCombs JL: Chromosome location of the human renin gene by in situ hybridization. Cytogenet Cell Genet 1987;45:55–57.
Ralph SJ, Thomas ML, Morton CC, Trowbridge IS: Structural variants of human T200 glycoprotein (leukocyte common antigen). EMBO J 1987; 6:1251–1257.
Seldin MF, Morse HC III, Reeves JP, Scribner CL, LeBoeuf RC, Steinberg AD: Genetic analysis of ‘autoimmune’gld mice. 1. Identification of a restriction fragment length polymorphism closely linked to thegld mutation within a conserved linkage group. J Exp Med 1988;167:688–693.
Seldin MF, Morse JC, LeBoeuf RC, Steinberg AD: Establishment of a molecular genetic map of distal mouse chromosome. I. Further definition of a conserved linkage group syngenic with human chromosome Iq. Genomics 1988;2:48–56.
Pardo-Manuel F, Rey-Campos J, Hillarp A, Dahlback B, Rodriquez de Cordoba S: Human genes for the a and b chains of complement C4b-binding protein are closely linked in a head-to-tail arrangement. Proc Natl Acad Sci USA 1990;87:4529–4532.
Dahlback B: Purification of human C4b-binding protein and formation of a complex with vitamin K-dependent protein S. Biochem J 1983;209:847–856.
Saeki T, Hirose S, Nakatsuka M, Kusunoki Y, Nagasawa S: Evidence that C4b-binding protein is an acute phase protein. Biochem Biophys Res Commun 1989;164:1446–1451.
Kidd J, Barnum SR: Biosynthesis of C4b-binding by HepG2 cells and human synovial fibroblasts. FASEB J 1990;4:2190.
Boerger LM, Morris PC, Thurnau GR, Esmon CT, Comp PC: Oral contraceptives and gender affect protein S status. Blood 1987;69:692–694.
Barnum SR, Dahlback B: C4b-binding protein, a regulatory component of the classical pathway of complement, is an acute phase protein and is elevated in systemic lupus erythematosus. Comp Inflamm 1990;7:71–77.
Moalic P, Gruel Y, Body G, Foloppe P, Delahousse B, Leroy J: Levels and plasma distribution of free and C4b-BP-bound protein S in human fetuses and full-term newborns. Thromb Res 1988;49:471–480.
Malm J, Bennhagen R, Holmberg L, Dahlback B: Plasma concentrations of C4b-binding protein and vitamin K-dependent protein S in term and preterm infants: Low levels of protein S-C4b-binding protein complexes. Br J Haematol 1988; 68:445–449.
Melissari E, Nicolaides KH, Scully MF, Kakkar VV: Protein S and C4b-binding protein in fetal and neonatal blood. Br J Haematol 1988;70:199–203.
Comp PC, Thurau GR, Welsh J, Esmon CT: Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986;68:881–885.
Melissari E, Kakkar VV: The effects of oestrogen administration on the plasma free protein S and C4b-binding protein. Thromb Res 1988;49:489–495.
Nagasawa S, Stroud RM: Mechanism of action of the C3b inactivator: Requirement for a high molecular weight cofactor (C3b–C4b INA cofactor) and production of a new C3b derivative (C3b′). Immunochemistry 1977;14:749–756.
Seva T, Nagasawa T: Limited proteolysis of complement protein C3b by regulatory enzyme C3b inactivator: Isolation and characterization of a biologically active fragment, C3d.g. J Biochem (Tokyo) 1985;97:373.
Medof ME, Nussenzweig V: Control of the function of substrate-bound C4b-C3b by the complement receptor CR1. J Exp Med 1984;159:1669–1685.
Fujita T, Nussenzweig V: The role of C4-binding protein and β1H in proteolysis of C4b and C3b. J Exp Med 1979;150:267–276.
Seya T, Holers VM, Atkinson JP: Purification and functional analysis of the polymorphic variants of the C3b/C4b receptor (CR1) and comparison with H, C4b-binding protein (C4bp), and decay accelerating factor (DAF). J Immunol 1985;135:2661–2667.
Pangburn MK, Schreiber RD, Muller-Eberhard HJ; Human complement C3b inactivator: Isolation, characterization, and demonstration of an absolute requirement for the serum protein b1H for cleavage of C3b and C4b in solution. J Exp Med 1977;146:257–270.
Pangburn MK, Muller-Eberhard HJ: Kinetic and thermodynamic analysis of the control of C3b by the complement regulatory proteins factors H and I. Biochemistry 1983;22:178–185.
Nagasawa S, Mizuguchi K, Ichihara C, Koyama J: Limited chymotryptic cleavage of human C4-binding protein: Isolation of a carbohydrate-containing core domain and an active fragment. J Biochem (Tokyo) 1982;92:11329–1332.
Reid KBM, Gagnon J: Human C4-binding protein: N-terminal amino acid sequence analysis and limited proteolysis by trypsin. FEBS Lett 1982;137:75–79.
Fujita T, Kamato T, Tamura N: Characterization of functional properties of C4-binding protein by monoclonal antibodies. J Immunol 1985;134:3320–3324.
Klickstein LB, Bartow TJ, Miletic V, Rabson LD, Smith JA, Fearon DT: Identification of distinct C3b and C4b recognition sites in the human C3b/C4b receptor (CR1, CD35) by deletion mutagenesis. J Exp Med 1988;168:1699–1717.
Lowell CA, Klickstein LB, Carter RH, Mitchell JA, Fearon DT, Ahearn JM: Mapping of the Epstein-Barr virus and C3dg binding sites to a common domain on complement receptor types. J Exp Med 1989;170:1931–1945.
Dahlback B, Stenflo J: High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc. Natl Acad Sci USA 1981;78:2512–2516.
Dahlback B, Hildebrand B: Degradation of human complement component C4b in the presence of the C4b-binding protein-protein S complex. Biochem J 1983;209:857–863.
Comp PC, Nixon RR, Cooper MR, Esmon CT: Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984;74:2082–2088.
Dahlback B: Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein. J Biol Chem 1986;261:12022–12027.
Nakatsuka M, Nagasawa S: Characterization of the interaction between human protein S and C4b-binding protein (C4BP). J Biochem (Tokyo) 1987;102:599–605.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Barnum, S.R. C4b-Binding protein, a regulatory protein of complement. Immunol Res 10, 28–42 (1991). https://doi.org/10.1007/BF02918165
Issue Date:
DOI: https://doi.org/10.1007/BF02918165