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Gene Review

C5  -  complement component 5

Homo sapiens

Synonyms: C3 and PZP-like alpha-2-macroglobulin domain-containing protein 4, C5D, C5a, C5b, CPAMD4, ...
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Disease relevance of C5


High impact information on C5

  • Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species [6].
  • Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection [6].
  • Its effect was enhanced by the third component (C3) of the complement system, but the fifth component (C5) had no effect [7].
  • Blockade of the C5a receptor rendered human monocytes unable to produce IL-12, mimicking blunted IL-12 production by macrophages from C5-deficient mice and providing a mechanism for the regulation of susceptibility to asthma by C5 [8].
  • Using microarray analysis of pulmonary gene expression and single nucleotide polymorphism-based genotyping, combined with quantitative trait locus analysis, we identified the gene encoding complement factor 5 (C5) as a susceptibility locus for allergen-induced airway hyperresponsiveness in a murine model of asthma [8].

Chemical compound and disease context of C5


Biological context of C5

  • We also identified a haplotype of the C5 gene that was protective against childhood BA (P = 1.4 x 10(-6)) and adult BA (P = 0.00063) [1].
  • Our results demonstrate that HNF1alpha plays a key role in the expression of C5 and C8A genes, two terminal complement component genes that are essential for the assembly of MAC as a result of complement activation [13].
  • Specific inhibition of C5a using mAb 137-26 binding the C5a moiety of C5 before cleavage prohibited CR3 up-regulation, phagocytosis, and oxidative burst but had no effect on C5b-9 (TCC) formation, lysis, and bacterial killing [14].
  • This interaction is specific and involves a single C5 binding site located on the beta-subunit of C8 [15].
  • Direct sequencing of all C5 exons displayed no mutation of obvious functional significance, except for an A to G transition in exon 10 predicting an exchange from lysine to arginine [16].

Anatomical context of C5

  • Finally, the C5 gene was found to be expressed in naive, GC, and memory B lymphocytes at both the mRNA and the protein level [17].
  • This study delineates a novel role for C5a as a regulator of the trafficking of human memory and naive B lymphocytes and supports the hypothesis that the B cells themselves may serve as source of C5 in secondary lymphoid tissues [17].
  • In this study we show that mice lacking the hepatic transcription factor hepatocyte nuclear factor 1alpha (HNF1alpha) fail to transcribe C5 and C8A complement genes [13].
  • Other marker systems excluded from linkage with C5 deficiency included the ceruloplasmin and Duffy loci at a recombination frequency of less than 15%, and the erythrocyte glyoxalase, MN, and Lewis loci at a recombination frequency of less than 5% [18].
  • Truncated C5 mRNA were not detected in Raji, MOLT-4, human fibroblast or U937 cells, although the full-length 6.0-kb transcript was seen in MOLT-4 cells [19].

Associations of C5 with chemical compounds

  • Expression and characterization of the C345C/NTR domains of complement components C3 and C5 [20].
  • The high binding affinities suggest that complexes composed of C5 bound to C6 or C7 exist in plasma before activation and may facilitate assembly of the complement membrane attack complex [20].
  • Complement components C3, C4, and C5 are members of the thioester-containing alpha-macroglobulin protein superfamily [20].
  • After enzymatic C3b coupling or standard amine C3b coupling, we analyzed and compared the binding of four C3b ligands to the surface: factor B, factor H, C5 and the soluble complement receptor 1 (sCR1, CD35) [21].
  • The C5a molecule is one of two spasmogenic fragments (i.e. C3a and C5a) released from serum components C3 and C5 during complement activation [22].

Physical interactions of C5

  • These results indicate that, like C6, the FIMs alone in C7 mediate reversible binding to C5 [23].
  • Properdin-stabilized C5 convertase sites were assembled on the non-activating cells of the alternative pathway, sheep erythrocytes (Es), and on the activating cells, desialated Es and rabbit erythrocytes (Er) [24].

Regulatory relationships of C5


Other interactions of C5

  • Polyclonal antibodies directed against C5c blocked the interaction of C5b-6 with C7, whereas antibodies directed against C5d inhibited the binding of C5 with C3b [26].
  • Recent studies have provided evidence that C3, C3a receptor, and C5 are linked to airway hyperresponsiveness [1].
  • There was a good correlation between expression of proteasome 20Salpha subunits, detected by western blotting, and C2 and C5 mRNA, showing that increased gene expression resulted in increased protein synthesis [5].
  • In patients with systemic lupus erythematosus, fractional catabolism and extravascular distribution of C3 and C5 were both increased, and there was marked extravascular catabolism of both proteins [27].
  • Comparison of the derived partial human C5 protein sequence with that previously determined for murine C3 and human alpha 2-macroglobulin has indicated regions of pronounced sequence similarity [3].

Analytical, diagnostic and therapeutic context of C5

  • Southern blot analyses indicated that the human C5 structural gene is large, complex, and is present in the human genome in a single copy, thereby demonstrating that the truncated C5 clones and mRNA are derived from a single C5 gene by alternative processing events [19].
  • Northern blot experiments demonstrated the presence of a 3.0-kb truncated C5 mRNA in adult human liver and a 4.8-kb truncated C5 mRNA in HepG2 cells in addition to the 6.0-kb full-length transcript [19].
  • Allele-specific PCR and sequence analyses demonstrated that the exon 1 mutation is present in only one of the C5 null genes in both the Rhode Island and North Carolina families, and the exon 36 mutation is contained in only one C5 null gene in the New York family [28].
  • Using surface plasmon resonance, we found that rC7-FIMs binds specifically to both C5 and the rC5-C345C domain with K(D) approximately 50 nM, and competes with C7 for binding to C5, as expected for an active domain [23].
  • Coding sequence alignment of the human C5 sequences with those of murine C5 indicated that 80% of the nucleotides and 79% of the amino acids were placed identically in the two species [29].


  1. 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]
  2. Complement C5 in experimental autoimmune encephalomyelitis (EAE) facilitates remyelination and prevents gliosis. Weerth, S.H., Rus, H., Shin, M.L., Raine, C.S. Am. J. Pathol. (2003) [Pubmed]
  3. Isolation and sequence analysis of a cDNA clone encoding the fifth complement component. Lundwall, A.B., Wetsel, R.A., Kristensen, T., Whitehead, A.S., Woods, D.E., Ogden, R.C., Colten, H.R., Tack, B.F. J. Biol. Chem. (1985) [Pubmed]
  4. A protective role for the fifth complement component (c5) in allergic airway disease. Drouin, S.M., Sinha, M., Sfyroera, G., Lambris, J.D., Wetsel, R.A. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  5. Increased expression of proteasome subunits in skeletal muscle of cancer patients with weight loss. Khal, J., Hine, A.V., Fearon, K.C., Dejong, C.H., Tisdale, M.J. Int. J. Biochem. Cell Biol. (2005) [Pubmed]
  6. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Hillebrandt, S., Wasmuth, H.E., Weiskirchen, R., Hellerbrand, C., Keppeler, H., Werth, A., Schirin-Sokhan, R., Wilkens, G., Geier, A., Lorenzen, J., Köhl, J., Gressner, A.M., Matern, S., Lammert, F. Nat. Genet. (2005) [Pubmed]
  7. 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]
  8. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Karp, C.L., Grupe, A., Schadt, E., Ewart, S.L., Keane-Moore, M., Cuomo, P.J., Köhl, J., Wahl, L., Kuperman, D., Germer, S., Aud, D., Peltz, G., Wills-Karp, M. Nat. Immunol. (2000) [Pubmed]
  9. Trypsin-activated complex of human factor B with cobra venom factor (CVF), cleaving C3 and C5 and generating a lytic factor for unsensitized guinea pig erythrocytes. I. Generation of the activated complex. Miyama, A., Kato, T., Horai, S., Yokoo, J., Kashiba, S. Biken journal. (1975) [Pubmed]
  10. Stereospecific elimination of hydrogen at C-10 in eicosapentaenoic acid during the conversion to leukotriene C5. Hammarström, S. J. Biol. Chem. (1983) [Pubmed]
  11. Bacteriochlorophyll c formation via the C5 pathway of 5-aminolevulinic acid synthesis in Chloroflexus aurantiacus. Oh-hama, T., Santander, P.J., Stolowich, N.J., Scott, A.I. FEBS Lett. (1991) [Pubmed]
  12. Intramedullary cystic teratoid tumor of the cervical spinal cord in association with a teratoma of the ovary. Cybulski, G.R., Von Roenn, K.A., Bailey, O.T. Surgical neurology. (1984) [Pubmed]
  13. Hepatocyte nuclear factor 1alpha controls the expression of terminal complement genes. Pontoglio, M., Pausa, M., Doyen, A., Viollet, B., Yaniv, M., Tedesco, F. J. Exp. Med. (2001) [Pubmed]
  14. Inhibition of C5a-induced inflammation with preserved C5b-9-mediated bactericidal activity in a human whole blood model of meningococcal sepsis. Sprong, T., Brandtzaeg, P., Fung, M., Pharo, A.M., Høiby, E.A., Michaelsen, T.E., Aase, A., van der Meer, J.W., van Deuren, M., Mollnes, T.E. Blood (2003) [Pubmed]
  15. Evidence that C5b recognizes and mediates C8 incorporation into the cytolytic complex of complement. Stewart, J.L., Kolb, W.P., Sodetz, J.M. J. Immunol. (1987) [Pubmed]
  16. Linking C5 deficiency to an exonic splicing enhancer mutation. Pfarr, N., Prawitt, D., Kirschfink, M., Schroff, C., Knuf, M., Habermehl, P., Mannhardt, W., Zepp, F., Fairbrother, W., Loos, M., Burge, C.B., Pohlenz, J. J. Immunol. (2005) [Pubmed]
  17. rC5a directs the in vitro migration of human memory and naive tonsillar B lymphocytes: implications for B cell trafficking in secondary lymphoid tissues. Ottonello, L., Corcione, A., Tortolina, G., Airoldi, I., Albesiano, E., Favre, A., D'Agostino, R., Malavasi, F., Pistoia, V., Dallegri, F. J. Immunol. (1999) [Pubmed]
  18. Hereditary C5 deficiency in man: genetic linkage studies. Rosenfeld, S.I., Weitkamp, L.R., Ward, F. J. Immunol. (1977) [Pubmed]
  19. Complete cDNA sequence of human complement pro-C5. Evidence of truncated transcripts derived from a single copy gene. Haviland, D.L., Haviland, J.C., Fleischer, D.T., Hunt, A., Wetsel, R.A. J. Immunol. (1991) [Pubmed]
  20. Expression and characterization of the C345C/NTR domains of complement components C3 and C5. Thai, C.T., Ogata, R.T. J. Immunol. (2003) [Pubmed]
  21. Complement C3b interactions studied with surface plasmon resonance technique. Jokiranta, T.S., Westin, J., Nilsson, U.R., Nilsson, B., Hellwage, J., Löfås, S., Gordon, D.L., Ekdahl, K.N., Meri, S. Int. Immunopharmacol. (2001) [Pubmed]
  22. Primary structural analysis of the polypeptide portion of human C5a anaphylatoxin. Polypeptide sequence determination and assignment of the oligosaccharide attachment site in C5a. Fernandez, H.N., Hugli, T.E. J. Biol. Chem. (1978) [Pubmed]
  23. Complement components C5 and C7: recombinant factor I modules of C7 bind to the C345C domain of C5. Thai, C.T., Ogata, R.T. J. Immunol. (2004) [Pubmed]
  24. Surface-dependent modulation by H of C5 cleavage by the cell-bound alternative pathway C5 convertase of human complement. Fischer, E., Kazatchkine, M.D. J. Immunol. (1983) [Pubmed]
  25. Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes. Vogt, W. Immunobiology (1996) [Pubmed]
  26. Formation and structure of the C5b-7 complex of the lytic pathway of complement. DiScipio, R.G. J. Biol. Chem. (1992) [Pubmed]
  27. Metabolism of the fifth component of complement, and its relation to metabolism of the third component, in patients with complement activation. Sissons, J.G., Liebowitch, J., Amos, N., Peters, D.K. J. Clin. Invest. (1977) [Pubmed]
  28. Inherited human complement C5 deficiency. Nonsense mutations in exons 1 (Gln1 to Stop) and 36 (Arg1458 to Stop) and compound heterozygosity in three African-American families. Wang, X., Fleischer, D.T., Whitehead, W.T., Haviland, D.L., Rosenfeld, S.I., Leddy, J.P., Snyderman, R., Wetsel, R.A. J. Immunol. (1995) [Pubmed]
  29. Molecular analysis of human complement component C5: localization of the structural gene to chromosome 9. Wetsel, R.A., Lemons, R.S., Le Beau, M.M., Barnum, S.R., Noack, D., Tack, B.F. Biochemistry (1988) [Pubmed]
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