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C6  -  complement component 6

Homo sapiens

 
 
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Disease relevance of C6

  • Two cDNA clones encoding C6 were isolated from a human liver library in the bacteriophage vector lambda gt11 [1].
  • No evidence for association of multiple sclerosis with the complement factors C6 and C7 [2].
  • In vivo, rats bearing grafts of either T-36B-10 or T-C6 rat gliomas at six subcutaneous sites received simultaneous intravenous injections of either [1-11C]glucose and [6-14C]glucose, or [1-14C]glucose and [6-11C]glucose [3].
  • Forty South African patients with homozygous deficiency of the sixth component of complement (C6) have been identified in an area where group B meningococcal meningitis is endemic; 22 of the 24 proband cases presented with recurrent meningococcal meningitis [4].
  • Heterogeneous susceptibility to neisserial infection was confirmed by following C6-deficient patients who presented with one or no Neisseria meningitidis infections [4].
 

High impact information on C6

  • This result was unexpected, as earlier studies mapped the C5b binding site, or a putative enzymatic region, to this part of C6 [5].
  • As assessed by HPLC, LTC4 composed greater than 85% of the C-6 peptide leukotriene released at any skin site, whereas little LTD4 or LTE4 was detected [6].
  • The amino acid sequence of the amino-terminal half of the complement protein C6 has been found to show overall structural homology with the homologous regions of the channel-forming proteins C7, C8 alpha, C8 beta, and C9 [1].
  • The sequence of the C6 protein reported here has 47-52% similarity with C7, C8 alpha, C8 beta, and C9, as well as 31-38% similarity with thrombospondin, thrombomodulin, and low density lipoprotein receptor [1].
  • In addition, two specific cysteine-rich segments common to the amino-terminal regions of C7, C8 alpha, C8 beta, and C9 also occur in their expected positions in C6, suggesting functional significance [1].
 

Chemical compound and disease context of C6

  • In vivo, tumor radioactivity levels normalized by plasma isotopic glucose levels showed that retained C-1 relative to C-6 radiolabeled glucose was significantly lower in both gliomas, 4.9% lower in T-36B-10 (p < 0.01) and 4.7% lower in T-C6 (p < 0.01) [3].
  • RESULTS: In vitro, the C-1/C-6 ratio for CO2 production from T-36B-10 monolayers was 8.8 +/- 0.4 (s.d.), in glioma slices it was 6.1 +/- 2.1 and in normal brain slices it was 1.1 +/- 0 [3].
 

Biological context of C6

  • Our findings suggest a possible relationship between oesophageal tumorigenesis and reduced expression of C6 and C7 mRNAs, which is probably caused by a change in gene expression regulation and not by genetic loss of the locus [7].
  • Data from this study show that the genes encoding the human terminal complement components C6, C7, and C9 define a cluster in the short arm of chromosome 5 [8].
  • These defects are associated with a characteristic set of polymorphic DNA markers in the C6/C7 region, forming a distinct haplotype [9].
  • Marker haplotype studies of the C6 and C7 gene region and Southern blots show that the Irish family with the splice defect also segregate for the deletion, which is not easily detected in heterozygotes [10].
  • Oligonucleotide probes derived from partial amino acid sequences of purified C6 were used to isolate cDNA clones from a human liver cDNA library [11].
 

Anatomical context of C6

  • However, the human hepatoma-derived cell line Hep-G2, which produces the majority of complement proteins, synthesizes traces of C6 [12].
  • Complement C6 is one of five plasma proteins that are incorporated into the lytic terminal complement complex on lipid membranes (C5b-9m) upon activation of the complement cascade [11].
  • Approximately 1 kb of C6 upstream sequence is shown to be sufficient to achieve tissue-specific expression of a luciferase reporter gene in two hepatic (Hep-G2 and Hep-3B) and two extrahepatic cell lines (fibroblast M1 and HeLa) in a manner similar to endogenous C6 [12].
  • There was a significantly binding of monoclonal anti-C3c antibodies, polyclonal anti-C5, anti-C6, anti-C7, anti-C8, and anti-C9 antibodies, and of a monoclonal antibody against a neoantigen of polymerized C9 to agarose beads incubated with the monocytes for 24, 48, 72 or 96 h [13].
  • We have used the rat C6 glial cell line as a model system to study the role of insulin-like growth factors (IGF) in neuroglial cells of the central nervous system (CNS) [14].
 

Associations of C6 with chemical compounds

  • The formation and structure of the complement cytolytic intermediary complex, C5b-7, were studied with the aim of determining the interactive regions of C5, C6, and C7 [15].
  • When mRNA expressions of other components were examined by means of semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in 10 tumour/normal pair specimens, significant reductions in C6 and C7 mRNAs were observed, while C3 and C5 mRNAs were enhanced in both normal and tumour tissues [7].
  • Complement protein C6 has been proposed by others to be a serine protease whose activity is obligatory for complement-directed cell lysis [16].
  • C6 is most similar in structure to complement C7, sharing 33.5% identical residues with C7 including all 56 cysteine residues [11].
  • C6 is a glycoprotein, and it has two oligosaccharide groups attached to asparagines located near the amino and the carboxyl termini of the molecule [17].
 

Regulatory relationships of C6

  • An immunoglobulin (no. 3637) directed against the rat IGF-II receptor blocked the degradation of [125I]IGF-II added to C6 glial cells, presumably by blocking receptor-mediated internalization [14].
 

Other interactions of C6

  • Chemical cross-linking using a cleavable radioiodinated photoreactive reagent revealed that both C6 and C7 associate preferentially with the alpha'-chain of C5b [15].
  • To establish the generality of protein C-mannosylation, and to learn more about its mechanism, the terminal components of the human complement system (C6, C7, C8,and C9), which contain multiple and complex recognition motifs, were examined [18].
  • Simultaneous occurrence of hereditary C6 and C2 deficiency in a French-Canadian family [19].
  • Hereditary complement (C6) deficiency associated with systemic lupus erythematosus, Sjögren's syndrome and hyperthyroidism [20].
 

Analytical, diagnostic and therapeutic context of C6

  • We have studied 20 individuals by Southern blot analysis with four C6 cDNA subclones to detect restriction fragment length polymorphisms (RFLPs) [8].
  • The tertiary structure of the C6 molecule was visualized by transmission electron microscopy; it has a sickle shape with dimensions of 144 x 66 A. The combined results are discussed and comparisons made with the other late acting components of complement and perforin [17].
  • The organization of secondary structural elements in C6 was elucidated using circular dichroism spectroscopy and an empirical method based on sequence analysis [17].
  • Acid-induced (C(5,6)a complex formation between C5 and C6 (protease-free) was demonstrated by ion-exchange fast protein liquid chromatography, reversed-phase high performance liquid chromatography, and reactive cytolytic activity in the presence of C7, C8, and C9; but no cleavage of the alpha-chain of C5 was observed [16].
  • Using polymerase chain reaction (PCR) we amplified a segment of the human C6 gene encompassing the presumably polymorphic codon [21].

References

  1. Structural homology of complement protein C6 with other channel-forming proteins of complement. Chakravarti, D.N., Chakravarti, B., Parra, C.A., Muller-Eberhard, H.J. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  2. No evidence for association of multiple sclerosis with the complement factors C6 and C7. Chataway, J., Sawcer, S., Sherman, D., Hobart, M., Fernie, B., Coraddu, F., Feakes, R., Broadley, S., Gray, J., Jones, H.B., Clayton, D., Goodfellow, P.N., Compston, A. J. Neuroimmunol. (1999) [Pubmed]
  3. Feasibility of imaging pentose cycle glucose metabolism in gliomas with PET: studies in rat brain tumor models. Spence, A.M., Graham, M.M., Muzi, M., Freeman, S.D., Link, J.M., Grierson, J.R., O'Sullivan, F., Stein, D., Abbott, G.L., Krohn, K.A. J. Nucl. Med. (1997) [Pubmed]
  4. Prophylaxis against Neisseria meningitidis infections and antibody responses in patients with deficiency of the sixth component of complement. Potter, P.C., Frasch, C.E., van der Sande, W.J., Cooper, R.C., Patel, Y., Orren, A. J. Infect. Dis. (1990) [Pubmed]
  5. Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6. Würzner, R., Hobart, M.J., Fernie, B.A., Mewar, D., Potter, P.C., Orren, A., Lachmann, P.J. J. Clin. Invest. (1995) [Pubmed]
  6. Accumulation of leukotriene C4 and histamine in human allergic skin reactions. Talbot, S.F., Atkins, P.C., Goetzl, E.J., Zweiman, B. J. Clin. Invest. (1985) [Pubmed]
  7. Reduction in the local expression of complement component 6 (C6) and 7 (C7) mRNAs in oesophageal carcinoma. Oka, R., Sasagawa, T., Ninomiya, I., Miwa, K., Tanii, H., Saijoh, K. Eur. J. Cancer (2001) [Pubmed]
  8. DNA polymorphisms and linkage relationship of the human complement component C6, C7, and C9 genes. Coto, E., Martínez-Naves, E., Domínguez, O., DiScipio, R.G., Urra, J.M., López-Larrea, C. Immunogenetics (1991) [Pubmed]
  9. Molecular bases of combined subtotal deficiencies of C6 and C7: their effects in combination with other C6 and C7 deficiencies. Fernie, B.A., Würzner, R., Orren, A., Morgan, B.P., Potter, P.C., Platonov, A.E., Vershinina, I.V., Shipulin, G.A., Lachmann, P.J., Hobart, M.J. J. Immunol. (1996) [Pubmed]
  10. Molecular bases of C7 deficiency: three different defects. Fernie, B.A., Orren, A., Sheehan, G., Schlesinger, M., Hobart, M.J. J. Immunol. (1997) [Pubmed]
  11. Complete primary structure and functional characterization of the sixth component of the human complement system. Identification of the C5b-binding domain in complement C6. Haefliger, J.A., Tschopp, J., Vial, N., Jenne, D.E. J. Biol. Chem. (1989) [Pubmed]
  12. Characterization of the human C6 promoter: requirement of the CCAAT enhancer binding protein binding site for C6 gene promoter activity. González, S., López-Larrea, C. J. Immunol. (1996) [Pubmed]
  13. Synthesis of complement components C5, C6, C7, C8 and C9 in vitro by human monocytes and assembly of the terminal complement complex. Hetland, G., Johnson, E., Falk, R.J., Eskeland, T. Scand. J. Immunol. (1986) [Pubmed]
  14. Rat C6 glial cells synthesize insulin-like growth factor I (IGF-I) and express IGF-I receptors and IGF-II/mannose 6-phosphate receptors. Kiess, W., Lee, L., Graham, D.E., Greenstein, L., Tseng, L.Y., Rechler, M.M., Nissley, S.P. Endocrinology (1989) [Pubmed]
  15. Formation and structure of the C5b-7 complex of the lytic pathway of complement. DiScipio, R.G. J. Biol. Chem. (1992) [Pubmed]
  16. Biochemical characterization of the human complement protein C6. Association with alpha-thrombin-like enzyme and absence of serine protease activity in cytolytically active C6. Chakravarti, D.N., Muller-Eberhard, H.J. J. Biol. Chem. (1988) [Pubmed]
  17. The molecular architecture of human complement component C6. DiScipio, R.G., Hugli, T.E. J. Biol. Chem. (1989) [Pubmed]
  18. The four terminal components of the complement system are C-mannosylated on multiple tryptophan residues. Hofsteenge, J., Blommers, M., Hess, D., Furmanek, A., Miroshnichenko, O. J. Biol. Chem. (1999) [Pubmed]
  19. Simultaneous occurrence of hereditary C6 and C2 deficiency in a French-Canadian family. Delâge, J.M., Lehner-Netsch, G., Lafleur, R., Simard, J., Brun, G., Prochazka, E. Immunology (1979) [Pubmed]
  20. Hereditary complement (C6) deficiency associated with systemic lupus erythematosus, Sjögren's syndrome and hyperthyroidism. Trapp, R.G., Mooney, E., Coleman, T.H., Forristal, J., Herman, J.H. J. Rheumatol. (1987) [Pubmed]
  21. Polymorphism of human complement component C6: an amino acid substitution (Glu/Ala) within the second thrombospondin repeat differentiates between the two common allotypes C6 A and C6 B. Dewald, G., Nöthen, M.M., Cichon, S. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
 
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