complement c8

Summary

Summary: A 150-kDa serum glycoprotein composed of three subunits with each encoded by a different gene (C8A; C8B; and C8G). This heterotrimer contains a disulfide-linked C8alpha-C8gamma heterodimer and a noncovalently associated C8beta chain. C8 is the next component to bind the C5-7 complex forming C5b-8 that binds COMPLEMENT C9 and acts as a catalyst in the polymerization of C9.

Top Publications

  1. Slade D, Lovelace L, Chruszcz M, Minor W, Lebioda L, Sodetz J. Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit. J Mol Biol. 2008;379:331-42 pubmed publisher
    ..Also observed is structural conservation of the MACPF signature motif Y/W-G-T/S-H-F/Y-X(6)-G-G in alphaMACPF and Plu-MACPF, and conservation of several key glycine residues known to be important for refolding and pore formation by CDCs. ..
  2. Hadders M, Beringer D, Gros P. Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense. Science. 2007;317:1552-4 pubmed
    ..The size of the MACPF domain is consistent with known C9 pore sizes. These data imply that these mammalian and bacterial cytolytic proteins share a common mechanism of membrane insertion. ..
  3. Lovelace L, Chiswell B, Slade D, Sodetz J, Lebioda L. Crystal structure of complement protein C8gamma in complex with a peptide containing the C8gamma binding site on C8alpha: implications for C8gamma ligand binding. Mol Immunol. 2008;45:750-6 pubmed
    ..These results suggest a role for C8alpha in regulating access to the putative C8gamma ligand binding site. ..
  4. Brannen C, Sodetz J. Incorporation of human complement C8 into the membrane attack complex is mediated by a binding site located within the C8beta MACPF domain. Mol Immunol. 2007;44:960-5 pubmed
    ..Furthermore, results indicate the principal binding sites for C8alpha and C5b-7 are located within this domain, and that C8beta binding specificity is not determined by the N- and C-terminal modules. ..
  5. Ng S, Rao A, Howard O, Sodetz J. The eighth component of human complement: evidence that it is an oligomeric serum protein assembled from products of three different genes. Biochemistry. 1987;26:5229-33 pubmed
  6. Musingarimi P, Plumb M, Sodetz J. Interaction between the C8 alpha-gamma and C8 beta subunits of human complement C8: role of the C8 beta N-terminal thrombospondin type 1 module and membrane attack complex/perforin domain. Biochemistry. 2002;41:11255-60 pubmed
    ..Results from activity assays suggest that residues within this segment also mediate binding and incorporation of C8 into the MAC. ..
  7. Scheurer B, Rittner C, Schneider P. Expression of the human complement C8 subunits is independently regulated by interleukin 1 beta, interleukin 6, and interferon gamma. Immunopharmacology. 1997;38:167-75 pubmed
    ..In contrast, only IFN-gamma but not IL-6 and IL-1 beta had an increasing effect on the expression of C8 beta. Thus the total amount of assembled functionally active C8 appears to be limited by the rate of C8 beta expression. ..
  8. Lockert D, Kaufman K, Chang C, Husler T, Sodetz J, Sims P. Identity of the segment of human complement C8 recognized by complement regulatory protein CD59. J Biol Chem. 1995;270:19723-8 pubmed
    ..Our data also suggest that optimal interaction of CD59 with this segment of human C8 alpha is influenced by N-terminal flanking sequence in C8 alpha and by human C8 beta, but is unaffected by C8 gamma. ..
  9. Steckel E, York R, Monahan J, Sodetz J. The eighth component of human complement. Purification and physicochemical characterization of its unusual subunit structure. J Biol Chem. 1980;255:11997-2005 pubmed
    ..These results indicate that C8 is an atypical serum protein with regard to both its subunit structure and denaturation characteristics. ..

More Information

Publications62

  1. Slade D, Chiswell B, Sodetz J. Functional studies of the MACPF domain of human complement protein C8alpha reveal sites for simultaneous binding of C8beta, C8gamma, and C9. Biochemistry. 2006;45:5290-6 pubmed
    ..Such a result suggests that this segment of C8alpha and corresponding segments of the other MAC family members are independently folded domains. ..
  2. Chan P, Simon Chazottes D, Mattei M, Guenet J, Salier J. Comparative mapping of lipocalin genes in human and mouse: the four genes for complement C8 gamma chain, prostaglandin-D-synthase, oncogene-24p3, and progestagen-associated endometrial protein map to HSA9 and MMU2. Genomics. 1994;23:145-50 pubmed
    ..MMU4, while their human counterparts map to the homologous HSA9q34 area where three other lipocalin genes for complement C8 gamma chain (C8G), progestagen-associated endometrial protein (PAEP), and prostaglandin D synthase (PTGDS) are ..
  3. Scibek J, Plumb M, Sodetz J. Binding of human complement C8 to C9: role of the N-terminal modules in the C8 alpha subunit. Biochemistry. 2002;41:14546-51 pubmed
    ..These results indicate that both N-terminal modules in C8alpha have a role in forming the principal binding site for C9 and that binding may be dependent on a cooperative interaction between these modules and the C8alpha MACPF domain. ..
  4. Plumb M, Sodetz J. An indel within the C8 alpha subunit of human complement C8 mediates intracellular binding of C8 gamma and formation of C8 alpha-gamma. Biochemistry. 2000;39:13078-83 pubmed
  5. Reinartz J, Hansch G, Kramer M. Complement component C7 is a plasminogen-binding protein. J Immunol. 1995;154:844-50 pubmed
    ..Based on these findings, an interaction is proposed between the complement system and the plasminogen activator system; a mechanism that may focus plasmin activity to structures that have been tagged by Ab and complement deposition. ..
  6. Pilzer D, Fishelson Z. Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis. Int Immunol. 2005;17:1239-48 pubmed
    ..As shown, mortalin can bind to complement C8 and C9 and is shed in vesicles containing C9 and complement MACs...
  7. Ellison R, Curd J, Kohler P, Reller L, Judson F. Underlying complement deficiency in patients with disseminated gonococcal infection. Sex Transm Dis. 1987;14:201-4 pubmed
  8. Schreck S, Parker C, Plumb M, Sodetz J. Human complement protein C8 gamma. Biochim Biophys Acta. 2000;1482:199-208 pubmed
    ..This review summarizes the current status of C8 gamma structure and function and the progress made from efforts to determine its role in the complement system. ..
  9. Haefliger J, Peitsch M, Jenne D, Tschopp J. Structural and functional characterization of complement C8 gamma, a member of the lipocalin protein family. Mol Immunol. 1991;28:123-31 pubmed
    ..It is therefore proposed that C8 gamma may act as a retinol transporting protein in plasma. ..
  10. Rao L, Li Y, Chen G, Zhou B, Schneider P, Zhang L. [Further study on heterogeneic basis of complement C8 beta deficiency]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2004;21:10-3 pubmed
    ..These two mutations, which create a termination codon, are sufficient to explain the complete C8 beta deficiency in both patients. ..
  11. Tschopp J, Chonn A, Hertig S, French L. Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9. J Immunol. 1993;151:2159-65 pubmed
    ..These results show that clusterin exerts its inhibitory effect by interacting with a structural motif common to C7, C8 alpha, and C9b. ..
  12. Wang W, Kirschfink M, Ruppel A. Schistosoma japonicum and S. mansoni cercariae: different effects of protein in medium, of mechanical stress, and of an intact complement system on in vitro transformation to schistosomula. Parasitol Res. 2006;99:269-74 pubmed
    ..mansoni were killed under these conditions. In conclusion, the dynamics of in vitro transformation of S. japonicum cercariae differ significantly from those of S. mansoni, and complement has a major transformation-promoting activity. ..
  13. Hobart M, Fernie B, DiScipio R. Structure of the human C7 gene and comparison with the C6, C8A, C8B, and C9 genes. J Immunol. 1995;154:5188-94 pubmed
    ..With the exception of exon 1, all intron/exon boundaries are preserved with respect to phase when compared with C6. ..
  14. Leath K, Johnson S, Roversi P, Hughes T, Smith R, Mackenzie L, et al. High-resolution structures of bacterially expressed soluble human CD59. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007;63:648-52 pubmed
    ..The presence/absence of this ligand is linked to alternate conformations of the amino acids implicated in C8/C9 binding. ..
  15. Stavrakoudis A. A disulfide linked model of the complement protein C8gamma complexed with C8alpha indel peptide. J Mol Model. 2009;15:165-71 pubmed publisher
    ..Average RMSD between backbone atoms of the indel peptide during the MD trajectory in comparison with the corresponding sequence of crystal structure of the C8alpha/gamma complex was found only 0.085 nm. ..
  16. Schlesinger M, Nave Z, Levy Y, Slater P, Fishelson Z. Prevalence of hereditary properdin, C7 and C8 deficiencies in patients with meningococcal infections. Clin Exp Immunol. 1990;81:423-7 pubmed
    ..This and other findings indicate that the type of complement abnormality found in association with meningococcal infections varies with the ethnic origin of the patient. ..
  17. Watts M, Dankert J, Morgan E. Isolation and characterization of a membrane-attack-complex-inhibiting protein present in human serum and other biological fluids. Biochem J. 1990;265:471-7 pubmed
    ..Depletion of MIP from plasma resulted in enhancement of the lytic capacity of the plasma on heterologous erythrocytes. ..
  18. Rose A, Kabiru J, Rose G. A rare case of orbital haemangiopericytoma arising in childhood. Orbit. 2013;32:384-6 pubmed publisher
    ..The patient underwent skin-sparing orbital exenteration with complete tumour excision; histology confirmed diagnosis of HPC. ..
  19. Coates L, Myles D. Prospects for atomic resolution and neutron crystallography in drug design. Curr Drug Targets. 2004;5:173-8 pubmed
    ..The benefits of atomic resolution X-ray data are discussed along with a number of structural examples of biomedically relevant proteins. The complementary role of neutron diffraction will also be discussed. ..
  20. Papanastasiou A, Zarkadis I. The gamma subunit of the eighth complement component (C8) in rainbow trout. Dev Comp Immunol. 2006;30:485-91 pubmed
    ..The lipocalin domain is present and all the cysteine residues are conserved. The trout C8gamma gene is probably present as a single copy in the trout genome showing a differential expression pattern among tissues investigated. ..
  21. Rinder C, Rinder H, Smith M, Tracey J, Fitch J, Li L, et al. Selective blockade of membrane attack complex formation during simulated extracorporeal circulation inhibits platelet but not leukocyte activation. J Thorac Cardiovasc Surg. 1999;118:460-6 pubmed
    ..These data also suggest a role for platelet activation or C5b-9 (or both) in the loss of monocytes and neutrophils to the extracorporeal circuit. ..
  22. Parker C, Sodetz J. Role of the human C8 subunits in complement-mediated bacterial killing: evidence that C8 gamma is not essential. Mol Immunol. 2002;39:453-8 pubmed
    ..Furthermore, they provide the first direct evidence that C8 gamma is not required for complement-mediated killing of Gram-negative bacteria. ..
  23. Weiland M, Qian Y, Sodetz J. Membrane pore formation by human complement: functional importance of the transmembrane ?-hairpin (TMH) segments of C8? and C9. Mol Immunol. 2014;57:310-6 pubmed publisher
    ..These results provide experimental evidence in support of the hypothesis that TMH segments in C8? and those predicted to be in C9 have a direct role in MAC membrane penetration and pore formation. ..
  24. Hunt L, Elzanowski A, Barker W. The homology of complement factor C8 gamma chain and alpha-1-microglobulin. Biochem Biophys Res Commun. 1987;149:282-8 pubmed
    ..Comparison of the C8 gamma chain with these proteins supports its homology to them and suggests a possible functional role. ..
  25. Haefliger J, Jenne D, Stanley K, Tschopp J. Structural homology of human complement component C8 gamma and plasma protein HC: identity of the cysteine bond pattern. Biochem Biophys Res Commun. 1987;149:750-4 pubmed
  26. Kaufman K, Snider J, Spurr N, Schwartz C, Sodetz J. Chromosomal assignment of genes encoding the alpha, beta, and gamma subunits of human complement protein C8: identification of a close physical linkage between the alpha and the beta loci. Genomics. 1989;5:475-80 pubmed
    ..Thus, the observed genetic linkage of alpha-gamma to beta must be determined solely by alpha. In accordance with these findings, the C8 loci should now be designated C8A, C8B, and C8G for alpha, beta and gamma, respectively. ..
  27. Haefliger J, Tschopp J, Nardelli D, Wahli W, Kocher H, Tosi M, et al. Complementary DNA cloning of complement C8 beta and its sequence homology to C9. Biochemistry. 1987;26:3551-6 pubmed
    ..In particular, the cysteine-rich domains and membrane-inserting regions of C9 are well conserved. These findings are discussed in relation to a possible mechanism of membrane attack complex formation. ..
  28. Hatanaka M, Shimizu A. [Immunologic tests: C6, C7, C8 and C9]. Nihon Rinsho. 2005;63 Suppl 7:92-4 pubmed
  29. Kallel Sellami M, Abdelmalek R, Zerzeri Y, Laadhar L, Blouin J, Zitouni M, et al. [Complement protein hereditary deficits during purulent meningitis: study of 61 adult Tunisian patients]. Arch Inst Pasteur Tunis. 2006;83:25-34 pubmed
    ..Our findings demonstrated a high prevalence of complement deficiency in Tunisia suggesting that screening for hereditary complement deficiency should be performed in case of bacterial meningitides and meningococcal disease patients...
  30. Baran K, Dunstone M, Chia J, Ciccone A, Browne K, Clarke C, et al. The molecular basis for perforin oligomerization and transmembrane pore assembly. Immunity. 2009;30:684-95 pubmed publisher
    ..Our study provides important insights into perforin's mechanism of action. ..
  31. Michelotti G, Snider J, Sodetz J. Genomic organization of human complement protein C8 alpha and further examination of its linkage to C8 beta. Hum Genet. 1995;95:513-8 pubmed
    ..Furthermore, they suggest that cDNA probes used earlier yielded misleading information because they encode exons that are distributed across large segments of genomic DNA. ..
  32. Barba G, Kaufmann T, Schneider P, Rittner C, Brai M. Polymorphism of the complement C8A and -B genes in two families with C8 beta deficiency and neisserial infections. Clin Immunol Immunopathol. 1994;72:83-9 pubmed
    Serum samples from members of two Italian families with complement C8 beta deficiency were studied by SDS-PAGE under nonreducing conditions and by IEF...
  33. Bellavia D, Schneider P, Rittner C, Malfitano G, Kaufmann T, Brai M. Detection of heterozygous C8 beta deficiency by PCR in a healthy Italian population. Exp Clin Immunogenet. 1996;13:173-80 pubmed
    ..It permitted to assess the real prevalence of the C8B mutated null allele in the general population free of ascertainment bias. ..
  34. Rogde S, Gedde Dahl T, Teisberg P, Jonassen R, Høyheim B, Olaisen B. Linkage and association studies with C8A and C8B RFLPs on chromosome 1. Ann Hum Genet. 1992;56:233-42 pubmed
    ..There was no evidence of allelic association between the C8A and C8B BamHI RFLPs in 62 unrelated haplotypes. ..
  35. Wickramaarachchi W, Whang I, Wan Q, Bathige S, De Zoysa M, Lim B, et al. Genomic characterization and expression analysis of complement component 8? and 8? in rock bream (Oplegnathus fasciatus). Dev Comp Immunol. 2013;39:279-92 pubmed publisher
    ..Full-length complement C8? (Rb-C8?) and C8? (Rb-C8?) sequences were identified from a cDNA library of rock bream (Oplegnathus fasciatus),..
  36. Lovelace L, Cooper C, Sodetz J, Lebioda L. Structure of human C8 protein provides mechanistic insight into membrane pore formation by complement. J Biol Chem. 2011;286:17585-92 pubmed publisher
    ..This leads to a model of the MAC that explains how C8-C9 and C9-C9 interactions could facilitate refolding and insertion of putative MACPF transmembrane ?-hairpins to form a circular pore. ..
  37. Sawant Mane S, Piddlesden S, Morgan B, Holers V, Koski C. CD59 homologue regulates complement-dependent cytolysis of rat Schwann cells. J Neuroimmunol. 1996;69:63-71 pubmed
  38. Howard O, Rao A, Sodetz J. Complementary DNA and derived amino acid sequence of the beta subunit of human complement protein C8: identification of a close structural and ancestral relationship to the alpha subunit and C9. Biochemistry. 1987;26:3565-70 pubmed
    ..For beta and alpha, the overall homology is 33% on the basis of identity and 53% when conserved substitutions are allowed. For beta and C9, the values are 26% and 47%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  39. Huang Y, Fedarovich A, Tomlinson S, Davies C. Crystal structure of CD59: implications for molecular recognition of the complement proteins C8 and C9 in the membrane-attack complex. Acta Crystallogr D Biol Crystallogr. 2007;63:714-21 pubmed
    ..This higher resolution structure of CD59 will facilitate a more precise dissection of its interactions with C8 and C9 and thus increase the likelihood of designing enhanced CD59-based therapeutics. ..
  40. Rogde S, Teisberg P, Olaisen B. C8A and C8B polymorphisms in Norwegians and Norwegian lapps. Hum Hered. 1989;39:81-8 pubmed
    ..C8B allele frequencies were also calculated from gene counts in the population material, but with due corrections for the C8BQ*0 frequency observed in the mother-child material. ..
  41. Rogde S, Høiby E, Teisberg P, Olaisen B. Genetic aspects of complement component C8 in Norwegian meningococcal disease patients. Scand J Infect Dis. 1990;22:673-9 pubmed
    ..All exhibited the same pattern, indicating that the C8B deficiency is not due to a major deletion in the C8B gene. ..
  42. Xu S, Venge P. Lipocalins as biochemical markers of disease. Biochim Biophys Acta. 2000;1482:298-307 pubmed
    ..of disease are orosomucoid, Protein HC (alpha(1)-microglobulin), apolipoprotein D, retinol-binding protein, complement C8 gamma, prostaglandin D synthase and human tear prealbumin, and these markers will be briefly reviewed in this ..
  43. Nakajima E, Itoh T, Suzuki K, Kawakami K, Takeda K, Onishi A, et al. Characterization, chromosomal localization, and genetic variation of the alpha subunit of porcine eighth component of complement. Anim Genet. 1998;29:377-80 pubmed
    ..Estimates of allele frequency of the 201 bp fragment were 0.22,.0.43,.0.04,.0.50,.0.58,.0.50,.0.98, and 0.91 in Landrace, Large White, Duroc, Berkshire, Jinhua, Crown Miniature Pig, wild boar, and Meishan, respectively. ..
  44. Arnold D, Roberts A, Thomas A, Ferry B, Morgan B, Chapel H. A novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent meningococcal meningitis. J Clin Immunol. 2009;29:691-5 pubmed publisher
    ..The parents each expressed one of these mutations, confirming compound heterozygosity. This is the first report of a duplication mutation in C8beta deficiency and extends the molecular heterogeneity of the disorder. ..
  45. He A, Yang J, Tang S, Wang C. Cloning and molecular characterization of complement component 1 inhibitor (C1INH) and complement component 8? (C8?) in Nile tilapia (Oreochromis niloticus). Fish Shellfish Immunol. 2013;35:1055-8 pubmed publisher
    ..The present study provided insights into the complement system and immune functions of Nile tilapia. ..
  46. Rao A, Howard O, Ng S, Whitehead A, Colten H, Sodetz J. Complementary DNA and derived amino acid sequence of the alpha subunit of human complement protein C8: evidence for the existence of a separate alpha subunit messenger RNA. Biochemistry. 1987;26:3556-64 pubmed
    ..Analysis of the carbohydrate composition indicates 1 or 2 asparagine-linked but no O-linked oligosaccharide chains, a result consistent with predictions from the amino acid sequence.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  47. Zhang L, Rittner C, Sodetz J, Schneider P, Kaufmann T. The eighth component of human complement: molecular basis of C8A (C81) polymorphism. Hum Genet. 1995;96:281-4 pubmed
  48. Kotnik V, Luznik Bufon T, Schneider P, Kirschfink M. Molecular, genetic, and functional analysis of homozygous C8 beta-chain deficiency in two siblings. Immunopharmacology. 1997;38:215-21 pubmed
    ..the common C-T mutation in the C8B genes is the genetic basis of C8 beta-chain deficiency in two members of this Bosnian family. ..
  49. Fernie King B, Seilly D, Willers C, Wurzner R, Davies A, Lachmann P. Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes. Immunology. 2001;103:390-8 pubmed
    ..We speculate that MAC inhibition may not be the sole function of SIC. ..
  50. Vakeva A, Morgan B, Tikkanen I, Helin K, Laurila P, Meri S. Time course of complement activation and inhibitor expression after ischemic injury of rat myocardium. Am J Pathol. 1994;144:1357-68 pubmed
    ..Deposition of C1 and late C components also starts during the early hours (2 to 4 hours) after ischemia. Subsequent loss of the protective CD59 antigen may initiate postinjury clearance of the irreversibly damaged tissue. ..
  51. Späth G, Ramadori G, Rittner C, Schneider P. Expression of the complement C8 genes during interleukin-6-mediated in vitro induction of the acute-phase response. Exp Clin Immunogenet. 1995;12:53-60 pubmed
    ..No evidence was obtained for an increased expression of IL-6 or IL-6 receptor mRNA thus excluding autoregulatory mechanisms of the cytokine in HepG2 cells. ..
  52. Kazantzi A, Sfyroera G, Holland M, Lambris J, Zarkadis I. Molecular cloning of the beta subunit of complement component eight of rainbow trout. Dev Comp Immunol. 2003;27:167-74 pubmed
    ..The protein encoded by the gene was identified by Western blotting using an anti-peptide antibody and was approximately 65kDa...
  53. Ninomiya H, Sims P. The human complement regulatory protein CD59 binds to the alpha-chain of C8 and to the "b"domain of C9. J Biol Chem. 1992;267:13675-80 pubmed
    ..Partial reduction of C8 alpha-gamma revealed that only C8 alpha polypeptide exhibited affinity for CD59, and no specific binding to the C8 gamma chain was detected.(ABSTRACT TRUNCATED AT 400 WORDS) ..