complement c3b

Summary

Summary: The larger fragment generated from the cleavage of COMPLEMENT C3 by C3 CONVERTASE. It is a constituent of the ALTERNATIVE PATHWAY C3 CONVERTASE (C3bBb), and COMPLEMENT C5 CONVERTASES in both the classical (C4b2a3b) and the alternative (C3bBb3b) pathway. C3b participates in IMMUNE ADHERENCE REACTION and enhances PHAGOCYTOSIS. It can be inactivated (iC3b) or cleaved by various proteases to yield fragments such as COMPLEMENT C3C; COMPLEMENT C3D; C3e; C3f; and C3g.

Top Publications

  1. Castiblanco Valencia M, Fraga T, Silva L, Monaris D, Abreu P, Strobel S, et al. Leptospiral immunoglobulin-like proteins interact with human complement regulators factor H, FHL-1, FHR-1, and C4BP. J Infect Dis. 2012;205:995-1004 pubmed publisher
    ..In conclusion, Lig proteins are multifunctional molecules, contributing to leptospiral adhesion and immune evasion. ..
  2. Lehtinen M, Rops A, Isenman D, van der Vlag J, Jokiranta T. Mutations of factor H impair regulation of surface-bound C3b by three mechanisms in atypical hemolytic uremic syndrome. J Biol Chem. 2009;284:15650-8 pubmed publisher
  3. Rawal N, Pangburn M. Formation of high-affinity C5 convertases of the alternative pathway of complement. J Immunol. 2001;166:2635-42 pubmed
    ..The catalytic rate of these convertases approaches maximum velocity, thereby switching the enzyme from cleavage of C3 to cleavage of C5, and production of the cytolytic C5b-9 complex. ..
  4. Yuste J, Sen A, Truedsson L, Jonsson G, Hyams C, Cohen J, et al. Impaired opsonization with complement and phagocytosis of Streptococcus pyogenes in sera from subjects with inherited C2 deficiency. Microbes Infect. 2010;12:626-34 pubmed publisher
    ..pyogenes. Impaired opsonisation with C3b/iC3b and phagocytosis was not related to reduced recognition of the bacteria by antibody. These data suggest that patients with C2 deficiency are at increased risk of S. pyogenes infections. ..
  5. Jozsi M, Heinen S, Hartmann A, Ostrowicz C, Hälbich S, Richter H, et al. Factor H and atypical hemolytic uremic syndrome: mutations in the C-terminus cause structural changes and defective recognition functions. J Am Soc Nephrol. 2006;17:170-7 pubmed
    ..The buried type B mutations seem to affect ligand interaction of factor H more severely than the surface-exposed mutations. ..
  6. Barthel D, Singh B, Riesbeck K, Zipfel P. Haemophilus influenzae uses the surface protein E to acquire human plasminogen and to evade innate immunity. J Immunol. 2012;188:379-85 pubmed publisher
    ..Thus, PE is a major plasminogen-binding protein of the Gram-negative bacterium H. influenzae, and when converted to plasmin, PE-bound plasmin aids in immune evasion and contributes to bacterial virulence. ..
  7. Janssen B, Christodoulidou A, McCarthy A, Lambris J, Gros P. Structure of C3b reveals conformational changes that underlie complement activity. Nature. 2006;444:213-6 pubmed
    ..These insights are important for the development of strategies to treat immune disorders that involve complement-mediated inflammation. ..
  8. Martinez Barricarte R, Heurich M, Valdes Cañedo F, Vazquez Martul E, Torreira E, Montes T, et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest. 2010;120:3702-12 pubmed publisher
  9. Oppermann M, Manuelian T, Jozsi M, Brandt E, Jokiranta T, Heinen S, et al. The C-terminus of complement regulator Factor H mediates target recognition: evidence for a compact conformation of the native protein. Clin Exp Immunol. 2006;144:342-52 pubmed

More Information

Publications61

  1. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267-79 pubmed
    ..Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments...
  2. Li K, Gor J, Perkins S. Self-association and domain rearrangements between complement C3 and C3u provide insight into the activation mechanism of C3. Biochem J. 2010;431:63-72 pubmed publisher
    ..The second dimerization of C3 and C3u may correspond to a dimer observed in one of the crystal structures of C3b. ..
  3. Jozsi M, Strobel S, Dahse H, Liu W, Hoyer P, Oppermann M, et al. Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood. 2007;110:1516-8 pubmed
    ..These results suggest that aHUS-associated FH autoantibodies mimic the effect of C-terminal FH mutations, as they inhibit the regulatory function of FH at cell surfaces by blocking its C-terminal recognition region. ..
  4. Schmidt C, Slingsby F, Richards A, Barlow P. Production of biologically active complement factor H in therapeutically useful quantities. Protein Expr Purif. 2011;76:254-63 pubmed publisher
    ..Furthermore, ease of genetic manipulation in P. pastoris would allow production of engineered FH versions with enhanced pharmacokinetic and pharmacodynamic properties. ..
  5. Roversi P, Johnson S, Caesar J, McLean F, Leath K, Tsiftsoglou S, et al. Structural basis for complement factor I control and its disease-associated sequence polymorphisms. Proc Natl Acad Sci U S A. 2011;108:12839-44 pubmed publisher
    ..In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors. ..
  6. Hocking H, Herbert A, Kavanagh D, Soares D, Ferreira V, Pangburn M, et al. Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations. J Biol Chem. 2008;283:9475-87 pubmed publisher
  7. Hair P, Ward M, Semmes O, Foster T, Cunnion K. Staphylococcus aureus clumping factor A binds to complement regulator factor I and increases factor I cleavage of C3b. J Infect Dis. 2008;198:125-33 pubmed publisher
    ..rClfA and the shed ClfA fragment increased factor I cleavage of C3b into inactive C3b. Our findings describe a new S. aureus mechanism for modification of host complement activities. ..
  8. Delvaeye M, Noris M, De Vriese A, Esmon C, Esmon N, Ferrell G, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345-57 pubmed publisher
    ..Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome. ..
  9. Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski M, Karpman D, et al. Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol Immunol. 2008;45:95-105 pubmed
    ..The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS. ..
  10. Furtado P, Huang C, Ihyembe D, Hammond R, Marsh H, Perkins S. The partly folded back solution structure arrangement of the 30 SCR domains in human complement receptor type 1 (CR1) permits access to its C3b and C4b ligands. J Mol Biol. 2008;375:102-18 pubmed
    ..We conclude that the inter-SCR linkers show structural features in common with those in FH, but differ from those in CR2, and the SCR arrangement in CR1 will permit C3b or C4b to access all three ligand sites. ..
  11. Yadav V, Pyaram K, Mullick J, Sahu A. Identification of hot spots in the variola virus complement inhibitor (SPICE) for human complement regulation. J Virol. 2008;82:3283-94 pubmed publisher
    ..Together, these results suggest that principally 4 of the 11 residues that differ between SPICE and VCP partake in its enhanced function against human complement...
  12. Haupt K, Reuter M, van den Elsen J, Burman J, Hälbich S, Richter J, et al. The Staphylococcus aureus protein Sbi acts as a complement inhibitor and forms a tripartite complex with host complement Factor H and C3b. PLoS Pathog. 2008;4:e1000250 pubmed publisher
    ..Thus, Sbi is a multifunctional bacterial protein, which binds host complement components Factor H and C3 as well as IgG and beta(2)-glycoprotein I and interferes with innate immune recognition. ..
  13. Ferreira V, Herbert A, Cortes C, McKee K, Blaum B, Esswein S, et al. The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. J Immunol. 2009;182:7009-18 pubmed publisher
    ..Taken together, our data suggest that disruption of a complex fH-self-surface recognition process, involving a balance of affinities for protein and physiological carbohydrate ligands, predisposes to aHUS. ..
  14. Yuste J, Ali S, Sriskandan S, Hyams C, Botto M, Brown J. Roles of the alternative complement pathway and C1q during innate immunity to Streptococcus pyogenes. J Immunol. 2006;176:6112-20 pubmed
    ..pyogenes and suggest that C1q-mediated innate immunity to at least some strains of S. pyogenes may involve mechanisms that are independent of C3b on the bacteria. ..
  15. Jokiranta T, Jaakola V, Lehtinen M, Pärepalo M, Meri S, Goldman A. Structure of complement factor H carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syndrome. EMBO J. 2006;25:1784-94 pubmed
    ..Therefore, the majority of the aHUS-associated mutations on the surface of FH19-20 interfere with the interaction between FH and C3b. This obviously leads to impaired control of complement attack on plasma-exposed cell surfaces in aHUS...
  16. Jokiranta T, Westin J, Nilsson U, Nilsson B, Hellwage J, Lofas S, et al. Complement C3b interactions studied with surface plasmon resonance technique. Int Immunopharmacol. 2001;1:495-506 pubmed
    ..On the other hand, both C5 and sCR1 bound to C3c, but not to C3d. In conclusion, this study shows that SPR is a powerful tool in analyzing and mapping the interactions of C3b with its multiple ligands. ..
  17. Cunnion K, Lee J, Frank M. Capsule production and growth phase influence binding of complement to Staphylococcus aureus. Infect Immun. 2001;69:6796-803 pubmed
    ..aureus cells, and about one-third of the bound C3 was shed from the staphylococcal surface as iC3b, regardless of the CP phenotype of the strain. Thus, the phase of growth and presence of capsule are critical to opsonization. ..
  18. Li B, Allendorf D, Hansen R, Marroquin J, Ding C, Cramer D, et al. Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway. J Immunol. 2006;177:1661-9 pubmed
    ..These results are important inasmuch as beta-glucan, an agent without evident toxicity, may be used to amplify tumor cell killing and may open new opportunities in the immunotherapy of cancer. ..
  19. Pangburn M, Pangburn K, Koistinen V, Meri S, Sharma A. Molecular mechanisms of target recognition in an innate immune system: interactions among factor H, C3b, and target in the alternative pathway of human complement. J Immunol. 2000;164:4742-51 pubmed
    ..The results reveal a complex molecular mechanism of discrimination between microbes and host in this ancient innate defense system and help explain the different rates and intensities of APC activation on different biological particles. ..
  20. 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. ..
  21. Jokiranta T, Hellwage J, Koistinen V, Zipfel P, Meri S. Each of the three binding sites on complement factor H interacts with a distinct site on C3b. J Biol Chem. 2000;275:27657-62 pubmed
    ..Multiple reciprocal interactions between C3b and fH can provide a basis for the different reactivity of the alternative pathway with different target structures. ..
  22. Le Buanec H, Gougeon M, Mathian A, Lebon P, Dupont J, Peltre G, et al. IFN-? and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells. Proc Natl Acad Sci U S A. 2011;108:18995-9000 pubmed publisher
    ..contact-mediated nTreg regulatory function is inhibited by inflammation, especially in the presence of the complement C3b receptor (CD46)...
  23. Hong F, Hansen R, Yan J, Allendorf D, Baran J, Ostroff G, et al. Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells. Cancer Res. 2003;63:9023-31 pubmed
    ..These data suggest that the therapeutic efficacy of mAbs known to activate complement (e.g., Herceptin, Rituxan, and Erbitux) could be significantly enhanced if they were combined with beta-glucan. ..
  24. 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. ..
  25. Craig M, Waitumbi J, Taylor R. Processing of C3b-opsonized immune complexes bound to non-complement receptor 1 (CR1) sites on red cells: phagocytosis, transfer, and associations with CR1. J Immunol. 2005;174:3059-66 pubmed
    ..We find that CR1, but not DAF, colocalizes with IgM mAb-C3b and IC-C3b substrates attached to glycophorin A. We observe that the binding of the IgM mAb-C3b to glycophorin A induces a novel unclustering of CR1. ..
  26. 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. ..
  27. Sartz L, Olin A, Kristoffersson A, Ståhl A, Johansson M, Westman K, et al. A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome. J Immunol. 2012;188:2030-7 pubmed publisher
    ..To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement. ..
  28. Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse H, Schirmer S, et al. Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood. 2009;114:2439-47 pubmed publisher
    ..These findings provide new insights into complement regulation on the cell surface and biosurfaces and likely define the role of CFHR1 in human diseases. ..
  29. Okemefuna A, Nan R, Miller A, Gor J, Perkins S. Complement factor H binds at two independent sites to C-reactive protein in acute phase concentrations. J Biol Chem. 2010;285:1053-65 pubmed publisher
    ..The SCR-16/20 site is novel and indicates the importance of the FH-CRP interaction for both age-related macular degeneration and atypical hemolytic uremic syndrome. ..
  30. Villiers M, Villiers C, Laharie A, Marche P. Different stimulating effects of complement C3b and complete Freund's adjuvant on antibody response. Immunopharmacology. 1999;42:151-7 pubmed
    ..HEL + CFA leads to better priming than HEL-C3b when mice are boosted with HEL-C3b. Thus, adjuvant effect of C3b is different from that of CFA, leading to more stable IgG production and better memory stimulation. ..
  31. Katschke K, Stawicki S, Yin J, Steffek M, Xi H, Sturgeon L, et al. Structural and functional analysis of a C3b-specific antibody that selectively inhibits the alternative pathway of complement. J Biol Chem. 2009;284:10473-9 pubmed publisher
    ..This study for the first time demonstrates the structural basis for complement inhibition by a C3b-selective antibody and provides insights into the molecular mechanisms of alternative pathway complement activation. ..
  32. Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, et al. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest. 2003;111:1181-90 pubmed
  33. Nilsson U. Deposition of C3b/iC3b leads to the concealment of antigens, immunoglobulins and bound C1q in complement-activating immune complexes. Mol Immunol. 2001;38:151-60 pubmed
    ..In biological terms, the concealment of bound IgG and C1q may reflect mechanisms by which complement down-regulates leukocyte responses stimulated by ligand-cell membrane receptor interactions. ..
  34. Chung M, Tonry J, Narayanan A, Manes N, Mackie R, Gutting B, et al. Bacillus anthracis interacts with plasmin(ogen) to evade C3b-dependent innate immunity. PLoS ONE. 2011;6:e18119 pubmed publisher
    ..anthracis through recruitment of PLG resulting in the enhancement of anti-complement and anti-opsonization properties of the pathogen. ..
  35. Sharp J, Cunnion K. Disruption of the alternative pathway convertase occurs at the staphylococcal surface via the acquisition of factor H by Staphylococcus aureus. Mol Immunol. 2011;48:683-90 pubmed publisher
    ..aureus surface inhibits complement-mediated opsonization via disruption of the alternative pathway convertase; thus, we report an immune-evasion mechanism not previously described for S. aureus. ..
  36. Bhattacharjee A, Lehtinen M, Kajander T, Goldman A, Jokiranta T. Both domain 19 and domain 20 of factor H are involved in binding to complement C3b and C3d. Mol Immunol. 2010;47:1686-91 pubmed publisher
    ..This explains why several aHUS-associated FH mutations are found within domain 19 in addition to domain 20. ..
  37. Liszewski M, Leung M, Schraml B, Goodship T, Atkinson J. Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome. Mol Immunol. 2007;44:1559-68 pubmed
    ..Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS. ..
  38. Lee Y, Lee K, Xu J, He Q, Chiu J, Lee W, et al. The embryotrophic activity of oviductal cell-derived complement C3b and iC3b, a novel function of complement protein in reproduction. J Biol Chem. 2004;279:12763-8 pubmed
    ..In conclusion, the present data showed that the oviduct produced C3/C3b, which was converted to iC3b to stimulate embryo development. ..
  39. Villiers M, Villiers C, Laharie A, Marche P. Amplification of the antibody response by C3b complexed to antigen through an ester link. J Immunol. 1999;162:3647-52 pubmed
  40. Cunnion K, Hair P, Buescher E. Cleavage of complement C3b to iC3b on the surface of Staphylococcus aureus is mediated by serum complement factor I. Infect Immun. 2004;72:2858-63 pubmed
    ..Purified factor H, a serum protein cofactor for factor I, did not enhance factor I-mediated cleavage of C3b. These findings suggest that C3b cleavage to iC3b on S. aureus is mediated by serum factor I and does not require factor H. ..
  41. Ferreira V, Pangburn M, Cortes C. Complement control protein factor H: the good, the bad, and the inadequate. Mol Immunol. 2010;47:2187-97 pubmed publisher
    ..e. cancer) by factor H is used as an immune evasion strategy. This review will focus on the current knowledge related to these versatile recognition properties of factor H. ..
  42. Harris C, Pettigrew D, Lea S, Morgan B. Decay-accelerating factor must bind both components of the complement alternative pathway C3 convertase to mediate efficient decay. J Immunol. 2007;178:352-9 pubmed
    ..These data provide new insights into the mechanisms involved in C3 convertase decay by DAF. ..
  43. 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. ..
  44. Park S, Shin Y, Kim C, Park H, Seong Y, Kim B, et al. Immune evasion of Enterococcus faecalis by an extracellular gelatinase that cleaves C3 and iC3b. J Immunol. 2008;181:6328-36 pubmed
    ..Taken together, it was suggested that GelE may represent a promising molecule for targeting human BSI associated with Ef. ..
  45. Cunnion K, Buescher E, Hair P. Serum complement factor I decreases Staphylococcus aureus phagocytosis. J Lab Clin Med. 2005;146:279-86 pubmed
    ..aureus surface, and thereby enhancing opsonophagocytosis, is a promising potential target for therapeutic intervention. ..
  46. 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
  47. Schmidt C, Herbert A, Kavanagh D, Gandy C, Fenton C, Blaum B, et al. A new map of glycosaminoglycan and C3b binding sites on factor H. J Immunol. 2008;181:2610-9 pubmed
    ..Contrary to expectations, none of several constructs encompassing modules from CCP 9 to 15 exhibited significant C3b binding in this assay. Thus, we propose a new functional map of factor H. ..
  48. Alcorlo M, Martinez Barricarte R, Fernandez F, Rodríguez Gallego C, Round A, Vega M, et al. Unique structure of iC3b resolved at a resolution of 24 Å by 3D-electron microscopy. Proc Natl Acad Sci U S A. 2011;108:13236-40 pubmed publisher
    ..These data further illustrate the extraordinary conformational versatility of C3 to accommodate a great diversity of functional activities. ..
  49. Hellwage J, Jokiranta T, Friese M, Wolk T, Kampen E, Zipfel P, et al. Complement C3b/C3d and cell surface polyanions are recognized by overlapping binding sites on the most carboxyl-terminal domain of complement factor H. J Immunol. 2002;169:6935-44 pubmed
    ..Mutations in this region, as recently reported in patients with familial hemolytic uremic syndrome, may lead to indiscriminatory C attack against self cells. ..
  50. Barilla LaBarca M, Liszewski M, Lambris J, Hourcade D, Atkinson J. Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells. J Immunol. 2002;168:6298-304 pubmed
    ..However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation. ..
  51. Nan R, Tetchner S, Rodriguez E, Pao P, Gor J, Lengyel I, et al. Zinc-induced self-association of complement C3b and Factor H: implications for inflammation and age-related macular degeneration. J Biol Chem. 2013;288:19197-210 pubmed publisher
    ..Zinc-induced precipitation may contribute to the initial development of sub-retinal pigment epithelial deposits in the retina as well as reducing the progression to advanced age-related macular degeneration in higher risk patients. ..
  52. Wu J, Wu Y, Ricklin D, Janssen B, Lambris J, Gros P. Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat Immunol. 2009;10:728-33 pubmed publisher
    ..Our results offer general models for complement regulation and provide structural explanations for disease-related mutations in the genes encoding both FH and C3b. ..