complement inactivator proteins


Summary: Serum proteins that negatively regulate the cascade process of COMPLEMENT ACTIVATION. Uncontrolled complement activation and resulting cell lysis is potentially dangerous for the host. The complement system is tightly regulated by inactivators that accelerate the decay of intermediates and certain cell surface receptors.

Top Publications

  1. Tyson K, Elkins C, de Silva A. A novel mechanism of complement inhibition unmasked by a tick salivary protein that binds to properdin. J Immunol. 2008;180:3964-8 pubmed
    ..S20NS is distinct from known decay accelerating factors, such as decay accelerating factor, complement receptor 1, and factor H, which directly interact with either C3b or cleaved factor B. ..
  2. Harris C, Williams A, Linton S, Morgan B. Coupling complement regulators to immunoglobulin domains generates effective anti-complement reagents with extended half-life in vivo. Clin Exp Immunol. 2002;129:198-207 pubmed
    ..The data demonstrate the potential of CRP-Ig as reagents for sustained therapy of inflammatory disorders, including arthritis, but emphasize the need for careful design of fusion proteins to retain function. ..
  3. Rooijakkers S, Milder F, Bardoel B, Ruyken M, Van Strijp J, Gros P. Staphylococcal complement inhibitor: structure and active sites. J Immunol. 2007;179:2989-98 pubmed
    ..Our data are a first step toward the development of a second generation molecule suitable for such therapeutic complement intervention. ..
  4. Kim D, Song W. Membrane complement regulatory proteins. Clin Immunol. 2006;118:127-36 pubmed
    ..In this article, we highlight recent advances on the in vivo biology of membrane complement regulatory proteins and discuss their relevance in human disease pathogenesis and therapeutics. ..
  5. Chen H, Ricklin D, Hammel M, Garcia B, McWhorter W, Sfyroera G, et al. Allosteric inhibition of complement function by a staphylococcal immune evasion protein. Proc Natl Acad Sci U S A. 2010;107:17621-6 pubmed publisher
    ..As this enzyme complex is critical for both activation and amplification of the complement response, its allosteric inhibition likely represents a fundamental contribution to the overall immune evasion strategy of S. aureus. ..
  6. Nunn M, Sharma A, Paesen G, Adamson S, Lissina O, Willis A, et al. Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. J Immunol. 2005;174:2084-91 pubmed
    ..OmCI is the first lipocalin family member shown to inhibit C and also the first natural inhibitor that specifically targets the C5 activation step...
  7. Blom A, Kask L, Ramesh B, Hillarp A. Effects of zinc on factor I cofactor activity of C4b-binding protein and factor H. Arch Biochem Biophys. 2003;418:108-18 pubmed
    ..Inhibition of the reaction seen at higher concentrations is due to aggregation of C4b/C3b. ..
  8. Morgan B, Harris C. Complement therapeutics; history and current progress. Mol Immunol. 2003;40:159-70 pubmed
  9. Song H, He C, Knaak C, Guthridge J, Holers V, Tomlinson S. Complement receptor 2-mediated targeting of complement inhibitors to sites of complement activation. J Clin Invest. 2003;111:1875-85 pubmed
    ..Finally, the in vivo validity of the targeting strategy was confirmed by the demonstration that CR2-DAF, but not soluble DAF, targets to the kidney in mouse models of lupus nephritis that are associated with renal complement deposition. ..

More Information


  1. Krych Goldberg M, Hauhart R, Porzukowiak T, Atkinson J. Synergy between two active sites of human complement receptor type 1 (CD35) in complement regulation: implications for the structure of the classical pathway C3 convertase and generation of more potent inhibitors. J Immunol. 2005;175:4528-35 pubmed
    ..These observations increase our understanding of the mechanism of DAA. In addition, a more potent decay-accelerating form of CR1 was generated. ..
  2. Schroeder H, Daix V, Gillet L, Renauld J, Vanderplasschen A. The paralogous salivary anti-complement proteins IRAC I and IRAC II encoded by Ixodes ricinus ticks have broad and complementary inhibitory activities against the complement of different host species. Microbes Infect. 2007;9:247-50 pubmed
    ..This report is the first description of paralogous anti-complement molecules encoded by a pathogen with broad and complementary inhibitory activities against the complement of different host species. ..
  3. Rooijakkers S, Wu J, Ruyken M, van Domselaar R, Planken K, Tzekou A, et al. Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat Immunol. 2009;10:721-7 pubmed publisher
    ..Understanding the mechanistic basis of the central complement-activation step and microbial immune evasion strategies targeting this step will aid in the development of complement therapeutics. ..
  4. Daix V, Schroeder H, Praet N, Georgin J, Chiappino I, Gillet L, et al. Ixodes ticks belonging to the Ixodes ricinus complex encode a family of anticomplement proteins. Insect Mol Biol. 2007;16:155-66 pubmed
    ..Finally, phylogenetic analyses demonstrate that ticks belonging to the Ixodes ricinus complex encode a family of relatively small anticomplement molecules undergoing diversification by positive Darwinian selection. ..
  5. Kask L, Trouw L, Dahlback B, Blom A. The C4b-binding protein-protein S complex inhibits the phagocytosis of apoptotic cells. J Biol Chem. 2004;279:23869-73 pubmed
    ..Although the presence of the C4BP-PS complex on apoptotic cells may lead to decreased phagocytosis, it may still be beneficial to the host, since it could prevent secondary necrosis because it inhibits further complement attack. ..
  6. Ricklin D, Tzekou A, Garcia B, Hammel M, McWhorter W, Sfyroera G, et al. A molecular insight into complement evasion by the staphylococcal complement inhibitor protein family. J Immunol. 2009;183:2565-74 pubmed publisher
    ..Our findings provide an important insight into complement evasion strategies by S. aureus and may act as a base for further functional studies. ..
  7. Webb J, Blom A, Dahlback B. The binding of protein S and the protein S-C4BP complex to neutrophils is apoptosis dependent. Blood Coagul Fibrinolysis. 2003;14:355-9 pubmed
    ..Thus, we conclude that binding of protein S and the C4BP-protein S complex to neutrophils is not cell specific, but rather apoptosis dependent. ..
  8. Jarva H, Ram S, Vogel U, Blom A, Meri S. Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis. J Immunol. 2005;174:6299-307 pubmed
    ..PorA-expressing strains were also more resistant to C lysis than PorA-negative strains in a serum bactericidal assay. Binding of C4bp thus helps Neisseria meningitidis to escape CP complement activation...
  9. Rooijakkers S, Ruyken M, Roos A, Daha M, Presanis J, Sim R, et al. Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases. Nat Immunol. 2005;6:920-7 pubmed
    ..As a highly active and small soluble protein that acts exclusively on surfaces, staphylococcal complement inhibitor may represent a promising anti-inflammatory molecule. ..
  10. Webb J, Blom A, Dahlback B. Vitamin K-dependent protein S localizing complement regulator C4b-binding protein to the surface of apoptotic cells. J Immunol. 2002;169:2580-6 pubmed
  11. Rehrig S, Fleming S, Anderson J, Guthridge J, Rakstang J, McQueen C, et al. Complement inhibitor, complement receptor 1-related gene/protein y-Ig attenuates intestinal damage after the onset of mesenteric ischemia/reperfusion injury in mice. J Immunol. 2001;167:5921-7 pubmed
  12. Blom A. A cluster of positively charged amino acids in the alpha-chain of C4b-binding protein (C4BP) is pivotal for the regulation of the complement system and the interaction with bacteria. Scand J Clin Lab Invest Suppl. 2000;233:37-49 pubmed
    ..We suggest that binding between C4b and C4BP is governed mostly by electrostatic interactions, while additional non-covalent forces cause tight binding of C4BP to streptococcal M proteins. ..
  13. Villoutreix B, Härdig Y, Wallqvist A, Covell D, Garcia de Frutos P, Dahlback B. Structural investigation of C4b-binding protein by molecular modeling: localization of putative binding sites. Proteins. 1998;31:391-405 pubmed
    ..An understanding of these intermolecular interactions should contribute to the rational design of potential therapeutic agents aiming at interfering specifically some of these protein-protein interactions. ..
  14. Smith G, Smith R. Membrane-targeted complement inhibitors. Mol Immunol. 2001;38:249-55 pubmed
    ..One membrane-targeted complement inhibitor has now entered clinical development and this class of second-generation agents may provide effective therapies for the treatment of a variety of disease states. ..
  15. Stoiber H, Pruenster M, Ammann C, Dierich M. Complement-opsonized HIV: the free rider on its way to infection. Mol Immunol. 2005;42:153-60 pubmed
    ..In the latter case HIV can be transmitted to cells susceptible for infection. This review discusses several aspects of C-HIV interactions and provides a model for the dynamics of this process. ..
  16. Upadhyay A, Burman J, Clark E, Leung E, Isenman D, van den Elsen J, et al. Structure-function analysis of the C3 binding region of Staphylococcus aureus immune subversion protein Sbi. J Biol Chem. 2008;283:22113-20 pubmed publisher
  17. Mizuno M, Morgan B. The possibilities and pitfalls for anti-complement therapies in inflammatory diseases. Curr Drug Targets Inflamm Allergy. 2004;3:87-96 pubmed
    ..Here we describe these new agents, their strengths and weaknesses and progress in testing the agents in relevant animal models. ..
  18. Ponnuraj K, Xu Y, Macon K, Moore D, Volanakis J, Narayana S. Structural analysis of engineered Bb fragment of complement factor B: insights into the activation mechanism of the alternative pathway C3-convertase. Mol Cell. 2004;14:17-28 pubmed
  19. Couvreur B, Beaufays J, Charon C, Lahaye K, Gensale F, Denis V, et al. Variability and action mechanism of a family of anticomplement proteins in Ixodes ricinus. PLoS ONE. 2008;3:e1400 pubmed publisher
    ..Looking for and detecting the different selection pressures involved will help in understanding the evolution of multigene families and hematophagy in arthropods. ..
  20. Blom A. Structural and functional studies of complement inhibitor C4b-binding protein. Biochem Soc Trans. 2002;30:978-82 pubmed
    ..We have localized interaction of C4BP with Neisseria gonorrhoeae, Bordetella pertussis, Streptococcus pyogenes and Escherichia coli to various regions of the alpha-chain. ..
  21. Blom A, Kask L, Dahlback B. Structural requirements for the complement regulatory activities of C4BP. J Biol Chem. 2001;276:27136-44 pubmed
    ..The results presented here elucidate the structural requirements of individual CCPs of C4BP, as well as their spatial arrangements within and between subunits for expression of full functional activity. ..
  22. Ram S, Cullinane M, Blom A, Gulati S, McQuillen D, Monks B, et al. Binding of C4b-binding protein to porin: a molecular mechanism of serum resistance of Neisseria gonorrhoeae. J Exp Med. 2001;193:281-95 pubmed
    ..This resulted in complete killing of these otherwise fully serum resistant strains in only 10% normal serum, underscoring the importance of C4bp in mediating gonococcal serum resistance. ..
  23. Blom A, Villoutreix B, Dahlback B. Complement inhibitor C4b-binding protein-friend or foe in the innate immune system?. Mol Immunol. 2004;40:1333-46 pubmed
    ..This contributes to the serum resistance and the pathogenicity of these bacteria. In this review, the structural requirements and functional importance of the interactions between C4BP and its various ligands are discussed. ..
  24. Gillet L, Daix V, Donofrio G, Wagner M, Koszinowski U, China B, et al. Development of bovine herpesvirus 4 as an expression vector using bacterial artificial chromosome cloning. J Gen Virol. 2005;86:907-17 pubmed
    ..This study demonstrates that BAC cloning and prokaryotic recombination technology are powerful tools for the development of BoHV-4 as an expression vector and for further fundamental studies of this gammaherpesvirus...
  25. Janssen B, Halff E, Lambris J, Gros P. Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition. J Biol Chem. 2007;282:29241-7 pubmed
    ..These insights are instrumental for further development of compstatin as a potential therapeutic. ..
  26. Prasadarao N, Blom A, Villoutreix B, Linsangan L. A novel interaction of outer membrane protein A with C4b binding protein mediates serum resistance of Escherichia coli K1. J Immunol. 2002;169:6352-60 pubmed
    ..A compelling observation in this study is that synthetic peptides corresponding to CCP3 sequences block the binding of C4bp to OmpA and also significantly enhance serum bactericidal activity. ..
  27. Hammel M, Sfyroera G, Pyrpassopoulos S, Ricklin D, Ramyar K, Pop M, et al. Characterization of Ehp, a secreted complement inhibitory protein from Staphylococcus aureus. J Biol Chem. 2007;282:30051-61 pubmed
    ..Our results suggest that increased inhibitory potency of Ehp relative to Efb-C is derived from the second C3-binding site in this new protein. ..
  28. Lublin D, Atkinson J. Decay-accelerating factor: biochemistry, molecular biology, and function. Annu Rev Immunol. 1989;7:35-58 pubmed
  29. Cochrane C, Muller Eberhard H, Aikin B. Depletion of plasma complement in vivo by a protein of cobra venom: its effect on various immunologic reactions. J Immunol. 1970;105:55-69 pubmed
  30. Dahlback B. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system. Thromb Haemost. 1991;66:49-61 pubmed
    ..As C4BP lacking the beta-chain is unable to bind protein S, the beta-chain is required for protein S binding, but not for the assembly of the alpha-chains during biosynthesis.(ABSTRACT TRUNCATED AT 400 WORDS) ..
  31. Rodriguez De Cordoba S, Perez Blas M, Ramos Ruiz R, Sanchez Corral P, Pardo Manuel de Villena F, Rey Campos J. The gene coding for the beta-chain of C4b-binding protein (C4BPB) has become a pseudogene in the mouse. Genomics. 1994;21:501-9 pubmed
    ..Thus, the characterization of the murine C4BPB gene documents the peculiar situation of a single-copy gene that is functional in humans but has become a pseudogene in the mouse.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  32. Takizawa H, Okada N, Okada H. Complement inhibitor of rat cell membrane resembling mouse Crry/p65. J Immunol. 1994;152:3032-8 pubmed
    ..512Ag was purified by use of an immunosorbent column prepared with mAb512. Partial sequencing of 512Ag peptides showed significant homology to mouse Crry/p65 indicating that 512Ag could be the rat counterpart of mouse Crry/p65. ..
  33. Dahlback B, Smith C, Muller Eberhard H. Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b. Proc Natl Acad Sci U S A. 1983;80:3461-5 pubmed
    ..C4b imaged as an irregular, relatively compact molecule. It was found to interact with the peripheral ends of the elongated subunits, suggesting seven C4b-binding sites per molecule of C4bp. ..
  34. Matsuguchi T, Okamura S, Aso T, Sata T, Niho Y. Molecular cloning of the cDNA coding for proline-rich protein (PRP): identity of PRP as C4b-binding protein. Biochem Biophys Res Commun. 1989;165:138-44 pubmed
    ..Furthermore, the reported molecular weights of the two proteins under both reduced and unreduced conditions were quite alike. These findings indicate that PRP is identical with C4bp. ..
  35. Hillarp A, Dahlback B. Novel subunit in C4b-binding protein required for protein S binding. J Biol Chem. 1988;263:12759-64 pubmed
    ..With protein S bound to C4BP, the 45-kDa subunit was protected from degradation by chymotrypsin, and the protein S binding site remained intact. These data suggest that the new subunit is directly involved in protein S binding. ..
  36. Lee J, Lee H, Nahm K, Jeon H, Hwang W, Paik N, et al. Effects of combined expression of human complement regulatory proteins and H-transferase on the inhibition of complement-mediated cytolysis in porcine embryonic fibroblasts. Transplant Proc. 2006;38:1618-21 pubmed
    ..These observations suggest that the combined expression of human CRPs and HT in the same insertional vector may be more effective in protecting porcine cells from human complement-mediated cytolysis. ..
  37. Soares M, Lin Y, Anrather J, Csizmadia E, Takigami K, Sato K, et al. Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nat Med. 1998;4:1073-7 pubmed
    ..We show here that the expression of the HO-1 gene is functionally associated with xenograft survival, and that rapid expression of HO-1 in cardiac xenografts can be essential to ensure long-term xenograft survival. ..
  38. Eldor A, Durst R, Hy Am E, Goldfarb A, Gillis S, Rachmilewitz E, et al. A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood. Br J Haematol. 1999;107:739-46 pubmed
    ..Thus, a chronic hypercoagulable state already exists in thalassaemia in childhood and may contribute to the cardiac and pulmonary anomalies and the thrombotic events which occur later. ..
  39. Spillner F, Kolln J, Bredehorst R. Inactivation of complement by recombinant human C3 derivatives. Adv Exp Med Biol. 2006;586:347-60 pubmed
  40. Wong P, Pfeffer B, Bernstein S, Chambers M, Chader G, Zakeri Z, et al. Clusterin protein diversity in the primate eye. Mol Vis. 2000;6:184-91 pubmed
    ..In addition, new insights were made in defining clusterin expression in ciliary body, cornea, and the retinal pigment epithelium. ..
  41. Sjöberg A, Trouw L, McGrath F, Hack C, Blom A. Regulation of complement activation by C-reactive protein: targeting of the inhibitory activity of C4b-binding protein. J Immunol. 2006;176:7612-20 pubmed
    ..We hypothesize that CRP limits excessive complement activation on targets via its interactions with both factor H and C4BP. ..
  42. Asghar S, Pasch M. Therapeutic inhibition of the complement system. Y2K update. Front Biosci. 2000;5:E63-81 pubmed
    ..It is hoped that in future therapeutic inhibition of complement will be one of the major approaches to combat many human diseases. ..
  43. Clough J. Copycat viruses outwit the immune system. Drug Discov Today. 2002;7:1067-8 pubmed
  44. Fritzinger D. Cancer research center hotline: complement depletion: use of human C3/cobra venom factor (CVF) chimeric proteins as therapeutic agents. Hawaii Med J. 2005;64:133-4, 137 pubmed
  45. Bao L, Haas M, Kraus D, Hack B, Rakstang J, Holers V, et al. Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice. J Am Soc Nephrol. 2003;14:670-9 pubmed
    ..Thus, inhibition of complement activation with Crry-Ig significantly reduces renal disease in MRL/lpr lupus mice. The data support the strategy of using recombinant complement C3 inhibitors to treat human lupus nephritis. ..
  46. Mqadmi A, Abdullah Y, Yazdanbakhsh K. Characterization of complement receptor 1 domains for prevention of complement-mediated red cell destruction. Transfusion. 2005;45:234-44 pubmed
    ..Our structure-function studies have characterized smaller CR1-based complement inhibitors for future development of structure-derived transfusion therapeutics. Our studies underscore the importance of testing CR1 inhibitors in vivo. ..
  47. Parks G, Alexander Miller M. Paramyxovirus activation and inhibition of innate immune responses. J Mol Biol. 2013;425:4872-92 pubmed publisher
    ..We discuss the importance of innate responses in DC following paramyxovirus infection and their consequences for the ability to mount and maintain antiviral T cells. ..
  48. Vani J, Elluru S, Negi V, Lacroix Desmazes S, Kazatchkine M, Bayry J, et al. Role of natural antibodies in immune homeostasis: IVIg perspective. Autoimmun Rev. 2008;7:440-4 pubmed publisher
    ..The therapeutic effects of IVIg most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy individuals. ..
  49. Cuida M, Legler D, Eidsheim M, Jonsson R. Complement regulatory proteins in the salivary glands and saliva of Sjögren's syndrome patients and healthy subjects. Clin Exp Rheumatol. 1997;15:615-23 pubmed
    ..These regulators may be involved in protecting the exocrine glands from complement mediated injury. ..
  50. Liu L, Persson J, Svensson M, Aldskogius H. Glial cell responses, complement, and clusterin in the central nervous system following dorsal root transection. Glia. 1998;23:221-38 pubmed
  51. Chi K, Eisenhauer E, Fazli L, Jones E, Goldenberg S, Powers J, et al. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst. 2005;97:1287-96 pubmed
    ..001 and Ptrend = .01, respectively). OGX-011 is well tolerated and reduces clusterin expression in primary prostate tumors. The optimal biologic dose for OGX-011 at the schedule used is 640 mg. ..
  52. Shoibonov B, Osipov A, Kryukova E, Zinchenko A, Lakhtin V, Tsetlin V, et al. Oxiagin from the Naja oxiana cobra venom is the first reprolysin inhibiting the classical pathway of complement. Mol Immunol. 2005;42:1141-53 pubmed
    ..Oxiagin is the first representative of snake venom reprolysins that inhibits the complement system, utilizing non-proteolytic inhibiting strategy. ..
  53. Fujii K, Hayashi T, Suzuki K. [C4b-binding protein]. Nihon Rinsho. 2004;62 Suppl 11:332-4 pubmed