| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
* Department of Bacteriology and Immunology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland;
Molecular Immunobiology Group and Department for Infection Biology, Hans Knoell Institute for Natural Products Research, Jena, Germany; and
Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
Factor H (FH) is a potent suppressor of the alternative pathway of C in plasma and when bound to sialic acid- or glycosaminoglycan-rich surfaces. Of the three interaction sites on FH for C3b, one interacts with the C3d part of C3b. In this study, we generated recombinant constructs of FH and FH-related proteins (FHR) to define the sites required for binding to C3d. In FH, the C3d-binding site was localized by surface plasmon resonance analysis to the most C-terminal short consensus repeat domain (SCR) 20. To identify amino acids of FH involved in binding to C3d and heparin, we compared the sequences of FH and FHRs and constructed a homology-based molecular model of SCR19–20 of FH. Subsequently, we created an SCR15–20 mutant with substitutions in five amino acids that were predicted to be involved in the binding interactions. These mutations reduced binding of the SCR15–20 construct to both C3b/C3d and heparin. Binding of the wild-type SCR15–20, but not the residual binding of the mutated SCR15–20, to C3d was inhibited by heparin. This indicates that the heparin- and C3d-binding sites are overlapping. Our results suggest that a region in the most C-terminal domain of FH is involved in target recognition by binding to C3b and surface polyanions. Mutations in this region, as recently reported in patients with familial hemolytic uremic syndrome, may lead to indiscriminatory C attack against self cells.
This article has been cited by other articles:
|
|
 |
|
  M. K. Liszewski, M. K. Leung, R. Hauhart, C. J. Fang, P. Bertram, and J. P. Atkinson Smallpox Inhibitor of Complement Enzymes (SPICE): Dissecting Functional Sites and Abrogating Activity J. Immunol., September 1, 2009; 183(5): 3150 - 3159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Strobel, P. F. Hoyer, C. J. Mache, E. Sulyok, W.-s. Liu, H. Richter, M. Oppermann, P. F. Zipfel, and M. Jozsi Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome Nephrol. Dial. Transplant., August 7, 2009; (2009) gfp388v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Lehtinen, A. L. Rops, D. E. Isenman, J. van der Vlag, and T. S. Jokiranta Mutations of Factor H Impair Regulation of Surface-bound C3b by Three Mechanisms in Atypical Hemolytic Uremic Syndrome J. Biol. Chem., June 5, 2009; 284(23): 15650 - 15658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Deban, H. Jarva, M. J. Lehtinen, B. Bottazzi, A. Bastone, A. Doni, T. S. Jokiranta, A. Mantovani, and S. Meri Binding of the Long Pentraxin PTX3 to Factor H: Interacting Domains and Function in the Regulation of Complement Activation J. Immunol., December 15, 2008; 181(12): 8433 - 8440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Siegel, J. Schreiber, K. Haupt, C. Skerka, V. Brade, M. M. Simon, B. Stevenson, R. Wallich, P. F. Zipfel, and P. Kraiczy Deciphering the Ligand-binding Sites in the Borrelia burgdorferi Complement Regulator-acquiring Surface Protein 2 Required for Interactions with the Human Immune Regulators Factor H and Factor H-like Protein 1 J. Biol. Chem., December 12, 2008; 283(50): 34855 - 34863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Q. Schmidt, A. P. Herbert, D. Kavanagh, C. Gandy, C. J. Fenton, B. S. Blaum, M. Lyon, D. Uhrin, and P. N. Barlow A New Map of Glycosaminoglycan and C3b Binding Sites on Factor H J. Immunol., August 15, 2008; 181(4): 2610 - 2619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-l. Stahl, F. Vaziri-Sani, S. Heinen, A.-C. Kristoffersson, K.-H. Gydell, R. Raafat, A. Gutierrez, O. Beringer, P. F. Zipfel, and D. Karpman Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation Blood, June 1, 2008; 111(11): 5307 - 5315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. G. Hocking, A. P. Herbert, D. Kavanagh, D. C. Soares, V. P. Ferreira, M. K. Pangburn, D. Uhrin, and P. N. Barlow Structure of the N-terminal Region of Complement Factor H and Conformational Implications of Disease-linked Sequence Variations J. Biol. Chem., April 4, 2008; 283(14): 9475 - 9487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jozsi, S. Strobel, H.-M. Dahse, W.-s. Liu, P. F. Hoyer, M. Oppermann, C. Skerka, and P. F. Zipfel Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome Blood, September 1, 2007; 110(5): 1516 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Caprioli, M. Noris, S. Brioschi, G. Pianetti, F. Castelletti, P. Bettinaglio, C. Mele, E. Bresin, L. Cassis, S. Gamba, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome Blood, August 15, 2006; 108(4): 1267 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. Banda, J. M. Thurman, D. Kraus, A. Wood, M. C. Carroll, W. P. Arend, and V. M. Holers Alternative Complement Pathway Activation Is Essential for Inflammation and Joint Destruction in the Passive Transfer Model of Collagen-Induced Arthritis J. Immunol., August 1, 2006; 177(3): 1904 - 1912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Herbert, D. Uhrin, M. Lyon, M. K. Pangburn, and P. N. Barlow Disease-associated Sequence Variations Congregate in a Polyanion Recognition Patch on Human Factor H Revealed in Three-dimensional Structure J. Biol. Chem., June 16, 2006; 281(24): 16512 - 16520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jozsi, S. Heinen, A. Hartmann, C. W. Ostrowicz, S. Halbich, H. Richter, A. Kunert, C. Licht, R. E. Saunders, S. J. Perkins, 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., January 1, 2006; 17(1): 170 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Mitsuyoshi, Y. Hu, and S. T. Test Role of Complement Receptor Type 2 and Endogenous Complement in the Humoral Immune Response to Conjugates of Complement C3d and Pneumococcal Serotype 14 Capsular Polysaccharide Infect. Immun., November 1, 2005; 73(11): 7311 - 7316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. S. Jokiranta, Z.-Z. Cheng, H. Seeberger, M. Jozsi, S. Heinen, M. Noris, G. Remuzzi, R. Ormsby, D. L. Gordon, S. Meri, et al. Binding of Complement Factor H to Endothelial Cells Is Mediated by the Carboxy-Terminal Glycosaminoglycan Binding Site Am. J. Pathol., October 1, 2005; 167(4): 1173 - 1181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sjoberg, P. Onnerfjord, M. Morgelin, D. Heinegard, and A. M. Blom The Extracellular Matrix and Inflammation: FIBROMODULIN ACTIVATES THE CLASSICAL PATHWAY OF COMPLEMENT BY DIRECTLY BINDING C1q J. Biol. Chem., September 16, 2005; 280(37): 32301 - 32308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Noris and G. Remuzzi Hemolytic Uremic Syndrome J. Am. Soc. Nephrol., April 1, 2005; 16(4): 1035 - 1050. [Full Text] [PDF]
|
|
|
|
 |
|
 V. K. Ganesh, S. A. Smith, G. J. Kotwal, and K. H. M. Murthy Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation PNAS, June 15, 2004; 101(24): 8924 - 8929. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Haas, F. R. Toapanta, J. A. Oliver, J. C. Poe, J. H. Weis, D. R. Karp, J. F. Bower, T. M. Ross, and T. F. Tedder Cutting Edge: C3d Functions as a Molecular Adjuvant in the Absence of CD21/35 Expression J. Immunol., May 15, 2004; 172(10): 5833 - 5837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-A. Dragon-Durey, V. Fremeaux-Bacchi, C. Loirat, J. Blouin, P. Niaudet, G. Deschenes, P. Coppo, W. Herman Fridman, and L. Weiss Heterozygous and Homozygous Factor H Deficiencies Associated with Hemolytic Uremic Syndrome or Membranoproliferative Glomerulonephritis: Report and Genetic Analysis of 16 Cases J. Am. Soc. Nephrol., March 1, 2004; 15(3): 787 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kraiczy, J. Hellwage, C. Skerka, H. Becker, M. Kirschfink, M. M. Simon, V. Brade, P. F. Zipfel, and R. Wallich Complement Resistance of Borrelia burgdorferi Correlates with the Expression of BbCRASP-1, a Novel Linear Plasmid-encoded Surface Protein That Interacts with Human Factor H and FHL-1 and Is Unrelated to Erp Proteins J. Biol. Chem., January 23, 2004; 279(4): 2421 - 2429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Pandiripally, L. Wei, C. Skerka, P. F. Zipfel, and D. Cue Recruitment of Complement Factor H-Like Protein 1 Promotes Intracellular Invasion by Group A Streptococci Infect. Immun., December 1, 2003; 71(12): 7119 - 7128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H P H Neumann, M Salzmann, B Bohnert-Iwan, T Mannuelian, C Skerka, D Lenk, B U Bender, M Cybulla, P Riegler, A Konigsrainer, et al. Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries J. Med. Genet., September 1, 2003; 40(9): 676 - 681. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
