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Gene Review

C3  -  complement component 3

Homo sapiens

Synonyms: AHUS5, ARMD9, ASP, C3 and PZP-like alpha-2-macroglobulin domain-containing protein 1, C3a, ...
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Disease relevance of C3


Psychiatry related information on C3

  • The levels and cellular localization of mRNA for complement C1q and C3 were examined by RNA gel blot and nonradioactive in situ hybridization in the frontal cortex of patients with Alzheimer's disease (AD) and age-matched controls [5].

High impact information on C3

  • Its effect was enhanced by the third component (C3) of the complement system, but the fifth component (C5) had no effect [6].
  • Human cells express C-regulatory proteins, CD46 and CD55, thereby circumventing attack by C3, a major effector of C [7].
  • Receptors for the Fc portion of immunoglobulins or for the third component of complement (C3) are present on a variety of circulating and fixed tissue cells including granulocytes, monocytes, lymphocytes and glomerular epithelial cells [8].
  • We recently reported that infection by HSV-1 induces both Fc and C3 receptors on human endothelial cells [8].
  • It is a cell-surface macromolecule (labelled with 125I and lactoperoxidase) which, in its isolated state, retains the ability to bind both C3 and C3b [9].

Chemical compound and disease context of C3

  • Linkage relationships of the insulin receptor gene with the complement component 3, LDL receptor, apolipoprotein C2 and myotonic dystrophy loci on chromosome 19 [10].
  • Liver biopsies of a 58-year-old clinically healthy patient with a hepatomegaly and intracisternal PAS-negative globular hyaline bodies were immunofluorescent-optically examined for the content of the complement components C 1 q, C 4, C 9, C 1-inactivator, C 3-activator [11].
  • We also report that solubilized gC-2, the genetically related glycoprotein specified by HSV-2, binds to iC3-Sepharose. mAb specific for gC-1 or gC-2 and mutant viral strains were used to identify the C3-binding glycoproteins [12].
  • In contrast, related Moraxella subspecies (n = 13) or other human pathogenic bacteria (n = 13) do not bind C3 or methylamine-treated C3 [13].
  • The ability of antigranulocyte antibody to fix the third component of complement (C3) to the granulocyte surface was investigated by an assay that quantitates the binding of monoclonal anti-C3 antibody to paraformaldehyde-fixed cells preincubated with Felty's syndrome serum in the presence of human complement [14].

Biological context of C3

  • These data provide evidence that regulated gamete-induced generation of C3 fragments and the binding of these fragments by selectively expressed receptors on sperm and oocytes may be an initial step in gamete interaction, leading to membrane fusion and fertilization [15].
  • C3b2-IgG complexes are formed during complement activation in serum by attachment of two C3b molecules (the proteolytically activated form of C3) to one IgG heavy chain (IgG HC) via ester bonds [16].
  • They also indicate that some or all of the C3 residues that are directly involved in, or contribute to, the structure of one of the CR1 and H binding sites are located within residues 727-768 [17].
  • Likewise, dimeric C3b is known to enhance complement receptor 1-dependent phagocytosis, and dimeric C3d (the smallest thioester-containing fragment of C3) linked to a protein antigen facilitates CR2-dependent B-cell proliferation [16].
  • Amino acid sequence data placed the Mr 17,000 fragment within residues 1385 to 1540 of the C3 sequence [18].

Anatomical context of C3


Associations of C3 with chemical compounds

  • This interaction is specific as evidenced by inhibition with nonconjugated virus, anti-CR2 antibodies, aggregated C3, and an antibody to the gp350 viral glycoprotein that the virus uses to bind to CR2 [19].
  • To characterize the interaction of VCP with C3 and C4 and understand the mechanism by which VCP inactivates complement, we have expressed VCP in a yeast expression system and compared the biologic activity of the purified protein to that of human factor H and complement receptor 1 (CR1) [22].
  • Expression and characterization of the C345C/NTR domains of complement components C3 and C5 [23].
  • In the presence of 1 M epsilon-amino-caproic acid (EACA) spontaneous C3 cleavage is considerably enhanced and accompanied by the appearance of biologically active C3a [24].
  • This is concluded from the finding that C3 inactivation is prevented by EDTA, by elimination of properdin factor B, and unimpaired in C4 deficient guinea pig serum [24].

Physical interactions of C3

  • The interactions of properdin with both surface-bound and fluid-phase C3 (the third component of complement) and its activation products have been investigated by using a purified preparation of the 'native' form [25].
  • Alterations in C3 activation and binding caused by phosphorylation by a casein kinase released from activated human platelets [26].
  • Sequencing of amino-terminal and internal peptides from the C3-binding protein disclosed a proline-rich region spanning approximately 20 amino acids and a signal peptide that had not been previously reported [27].
  • These results clearly demonstrate that C3/C4 gene duplication and linkage between the C4 gene and the major histocompatibility complex predate mammalian/amphibian divergence [28].
  • A protein drp90 encoded on the leftwards strand of soybean nodule urate oxidase cDNA binds to a regulatory sequence in leghemoglobin C3 gene [29].

Enzymatic interactions of C3

  • C3 that had been phosphorylated with platelet casein kinase was tested for its susceptibility to cleavage by trypsin or the classical and alternative pathway convertases and its binding to EAC and IgG [26].
  • In this communication, we report that MASP is unique in having the proteolytic capacity to cleave C3 with subsequent activation of the alternative pathway, a capacity which C1s lacks [30].
  • Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests [31].

Regulatory relationships of C3

  • CD40 ligation is able to enhance C3 secretion by PTEC [32].
  • Inhibition of NF-kappaB offset CD40L-induced C3 secretion by 70% [32].
  • RESULTS: Granulocyte adsorption to CA beads required plasma IgG, the complement C3 and was inhibited by an antibody to leucocytes CD18 [33].
  • In serum the inhibitory effect of 1 M EACA on C3bINA appears to allow escape of the properdin system from its control and thus to increase its net activity toward C3 despite inhibition of the enzymic reactions proper [24].
  • The greatest magnitude of C3 secretion was induced by the combination of IL-1beta and IL-6 [34].

Other interactions of C3

  • The structure supports a model whereby the transition of native C3 to its functionally active state involves the disruption of a complementary domain interface and provides insight into the basis for the interaction between C3d and CR2 [35].
  • Rare variants were observed in the C3, Tf, and Pi systems [36].
  • In addition, antibodies to both MCP and C3 significantly inhibited penetration of hamster oocytes by human sperm [15].
  • Complement components C3, C4, and C5 are members of the thioester-containing alpha-macroglobulin protein superfamily [23].
  • MT1-MMP proteolysis liberates the deposited C3 activation fragments from the cell surface [37].

Analytical, diagnostic and therapeutic context of C3


  1. Weight gain in relation to plasma levels of complement factor 3: results from a population-based cohort study. Engström, G., Hedblad, B., Janzon, L., Lindgärde, F. Diabetologia (2005) [Pubmed]
  2. Relationship between Epstein-Barr virus (EBV)-production and the loss of the EBV receptor/complement receptor complex in a series of sublines derived from the same original Burkitt's lymphoma. Klein, G., Yefenof, E., Falk, K., Westman, A. Int. J. Cancer (1978) [Pubmed]
  3. Variations in the C3, C3a receptor, and C5 genes affect susceptibility to bronchial asthma. Hasegawa, K., Tamari, M., Shao, C., Shimizu, M., Takahashi, N., Mao, X.Q., Yamasaki, A., Kamada, F., Doi, S., Fujiwara, H., Miyatake, A., Fujita, K., Tamura, G., Matsubara, Y., Shirakawa, T., Suzuki, Y. Hum. Genet. (2004) [Pubmed]
  4. Activation of classical pathway complement in chronic inflammation. Elevated levels of circulating C3d and C4d split products in rheumatoid arthritis and Crohn's disease. Petersen, N.E., Elmgreen, J., Teisner, B., Svehag, S.E. Acta medica Scandinavica. (1988) [Pubmed]
  5. Complement C1q and C3 mRNA expression in the frontal cortex of Alzheimer's patients. Fischer, B., Schmoll, H., Riederer, P., Bauer, J., Platt, D., Popa-Wagner, A. J. Mol. Med. (1995) [Pubmed]
  6. Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. Toyka, K.V., Drachman, D.B., Griffin, D.E., Pestronk, A., Winkelstein, J.A., Fishbeck, K.H., Kao, I. N. Engl. J. Med. (1977) [Pubmed]
  7. A novel protein that participates in nonself discrimination of malignant cells by homologous complement. Matsumoto, M., Takeda, J., Inoue, N., Hara, T., Hatanaka, M., Takahashi, K., Nagasawa, S., Akedo, H., Seya, T. Nat. Med. (1997) [Pubmed]
  8. Glycoprotein C of herpes simplex virus 1 acts as a receptor for the C3b complement component on infected cells. Friedman, H.M., Cohen, G.H., Eisenberg, R.J., Seidel, C.A., Cines, D.B. Nature (1984) [Pubmed]
  9. Isolation of a biologically active macrophage receptor for the third component of complement. Schneider, R.J., Kulczycki, A., Law, S.K., Atkinson, J.P. Nature (1981) [Pubmed]
  10. Linkage relationships of the insulin receptor gene with the complement component 3, LDL receptor, apolipoprotein C2 and myotonic dystrophy loci on chromosome 19. Shaw, D.J., Meredith, A.L., Brook, J.D., Sarfarzi, M., Harley, H.G., Huson, S.M., Bell, G.I., Harper, P.S. Hum. Genet. (1986) [Pubmed]
  11. Storage of the complement components C4, C3, and C 3-activator in the human liver as PAS-negative globular hyaline bodies. Storch, W., Riedel, H., Trautmann, B., Justus, J., Hiemann, D. Experimental pathology. (1982) [Pubmed]
  12. Herpes simplex virus glycoproteins gC-1 and gC-2 bind to the third component of complement and provide protection against complement-mediated neutralization of viral infectivity. McNearney, T.A., Odell, C., Holers, V.M., Spear, P.G., Atkinson, J.P. J. Exp. Med. (1987) [Pubmed]
  13. Ionic binding of C3 to the human pathogen Moraxella catarrhalis is a unique mechanism for combating innate immunity. Nordström, T., Blom, A.M., Tan, T.T., Forsgren, A., Riesbeck, K. J. Immunol. (2005) [Pubmed]
  14. Activation of human complement by immunoglobulin G antigranulocyte antibody. Rustagi, P.K., Currie, M.S., Logue, G.L. J. Clin. Invest. (1982) [Pubmed]
  15. The role of complement component C3b and its receptors in sperm-oocyte interaction. Anderson, D.J., Abbott, A.F., Jack, R.M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  16. C3b2-IgG complexes retain dimeric C3 fragments at all levels of inactivation. Jelezarova, E., Luginbuehl, A., Lutz, H.U. J. Biol. Chem. (2003) [Pubmed]
  17. Dissection of CR1, factor H, membrane cofactor protein, and factor B binding and functional sites in the third complement component. Lambris, J.D., Lao, Z., Oglesby, T.J., Atkinson, J.P., Hack, C.E., Becherer, J.D. J. Immunol. (1996) [Pubmed]
  18. A 34-amino acid peptide of the third component of complement mediates properdin binding. Daoudaki, M.E., Becherer, J.D., Lambris, J.D. J. Immunol. (1988) [Pubmed]
  19. Infection of human thymocytes by Epstein-Barr virus. Watry, D., Hedrick, J.A., Siervo, S., Rhodes, G., Lamberti, J.J., Lambris, J.D., Tsoukas, C.D. J. Exp. Med. (1991) [Pubmed]
  20. Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines. Cole, J.L., Housley, G.A., Dykman, T.R., MacDermott, R.P., Atkinson, J.P. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  21. Mapping of the C3d receptor (CR2)-binding site and a neoantigenic site in the C3d domain of the third component of complement. Lambris, J.D., Ganu, V.S., Hirani, S., Müller-Eberhard, H.J. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  22. Interaction of vaccinia virus complement control protein with human complement proteins: factor I-mediated degradation of C3b to iC3b1 inactivates the alternative complement pathway. Sahu, A., Isaacs, S.N., Soulika, A.M., Lambris, J.D. J. Immunol. (1998) [Pubmed]
  23. Expression and characterization of the C345C/NTR domains of complement components C3 and C5. Thai, C.T., Ogata, R.T. J. Immunol. (2003) [Pubmed]
  24. Cleavage of the third complement component (C3) and generation of the spasmogenic peptide, C3a, in human serum via the properdin pathway: demonstration of inhibitory as well as enhancing effects of epsilon-amino-caproic acid. Vogt, W., Schmidt, G., Lynen, R., Dieminger, L. J. Immunol. (1975) [Pubmed]
  25. Analysis of the interactions between properdin, the third component of complement (C3), and its physiological activation products. Farries, T.C., Lachmann, P.J., Harrison, R.A. Biochem. J. (1988) [Pubmed]
  26. Alterations in C3 activation and binding caused by phosphorylation by a casein kinase released from activated human platelets. Ekdahl, K.N., Nilsson, B. J. Immunol. (1999) [Pubmed]
  27. Novel purification scheme and functions for a C3-binding protein from Streptococcus pneumoniae. Cheng, Q., Finkel, D., Hostetter, M.K. Biochemistry (2000) [Pubmed]
  28. Fourth component of Xenopus laevis complement: cDNA cloning and linkage analysis of the frog MHC. Mo, R., Kato, Y., Nonaka, M., Nakayama, K., Takahashi, M. Immunogenetics (1996) [Pubmed]
  29. A protein drp90 encoded on the leftwards strand of soybean nodule urate oxidase cDNA binds to a regulatory sequence in leghemoglobin C3 gene. Bergmann, J.E., Preddie, E., Cortes, L., Brousseau, R. Nucleic Acids Res. (1991) [Pubmed]
  30. Cleavage of the third component of complement (C3) by mannose-binding protein-associated serine protease (MASP) with subsequent complement activation. Matsushita, M., Fujita, T. Immunobiology (1995) [Pubmed]
  31. Proteolysis of C3 on U937 cell plasma membranes. Purification of cathepsin G. Maison, C.M., Villiers, C.L., Colomb, M.G. J. Immunol. (1991) [Pubmed]
  32. CD40 ligand increases complement C3 secretion by proximal tubular epithelial cells. Castellano, G., Cappiello, V., Fiore, N., Pontrelli, P., Gesualdo, L., Schena, F.P., Montinaro, V. J. Am. Soc. Nephrol. (2005) [Pubmed]
  33. Adhesion dependent release of hepatocyte growth factor and interleukin-1 receptor antagonist from human blood granulocytes and monocytes: evidence for the involvement of plasma IgG, complement C3 and beta2 integrin. Takeda, Y., Shiobara, N., Saniabadi, A.R., Adachi, M., Hiraishi, K. Inflamm. Res. (2004) [Pubmed]
  34. Comparative effects of cytokines and cytokine combinations on complement component C3 secretion by HepG2 cells. Andrews, E., Feldhoff, P., Feldhoff, R., Lassiter, H. Cytokine (2003) [Pubmed]
  35. X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2. Nagar, B., Jones, R.G., Diefenbach, R.J., Isenman, D.E., Rini, J.M. Science (1998) [Pubmed]
  36. Serum protein polymorphisms in four populations of Afghanistan. Rahimi, A.G., Goedde, H.W., Flatz, G., Kaifie, S., Benkmann, H.G., Delbrück, H. Am. J. Hum. Genet. (1977) [Pubmed]
  37. Cellular membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves C3b, an essential component of the complement system. Rozanov, D.V., Savinov, A.Y., Golubkov, V.S., Postnova, T.I., Remacle, A., Tomlinson, S., Strongin, A.Y. J. Biol. Chem. (2004) [Pubmed]
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