scholarly journals Putative Coiled-Coil Structural Elements of the BBA68 Protein of Lyme Disease Spirochetes Are Required for Formation of Its Factor H Binding Site

2005 ◽  
Vol 187 (4) ◽  
pp. 1317-1323 ◽  
Author(s):  
John V. McDowell ◽  
Matthew E. Harlin ◽  
Elizabeth A. Rogers ◽  
Richard T. Marconi
Keyword(s):  
Lyme Disease ◽  
Binding Site ◽  
Immune Evasion ◽  
Coiled Coil ◽  
Factor H ◽  
Regulatory Proteins ◽  
Structural Elements ◽  
Binding Ability ◽  
Complement Regulatory Proteins ◽  
Factor I

ABSTRACT Factor H and factor H like-protein 1 (FHL-1) are complement regulatory proteins that serve as cofactors for the factor I-mediated cleavage of C3b. Some Lyme disease and relapsing fever spirochete species bind factor H to their surface to facilitate immune evasion. The Lyme disease spirochetes produce several factor H binding proteins (FHBPs) that form two distinct classes. Class I FHBPs (OspE orthologs and paralogs) bind only factor H, while class II FHBPs (BBA68) bind both factor H and FHL-1. BBA68 belongs to a large paralogous protein family, and of these paralogs, BBA69 is the member most closely related to BBA68. To determine if BBA69 can also bind factor H, recombinant protein was generated and tested for factor H binding. BBA69 did not exhibit factor H binding ability, suggesting that among family 54 paralogs, factor H binding is unique to BBA68. To identify the determinants of BBA68 that are involved in factor H binding, truncation and site-directed mutational analyses were performed. These analyses revealed that the factor H binding site is discontinuous and provide strong evidence that coiled-coil structural elements are involved in the formation of the binding site.

scholarly journals Demonstration of Factor H-Like Protein 1 Binding to Treponema denticola, a Pathogen Associated with Periodontal Disease in Humans

2005 ◽  
Vol 73 (11) ◽  
pp. 7126-7132 ◽  
Author(s):  
John V. McDowell ◽  
Justin Lankford ◽  
Lola Stamm ◽  
Tania Sadlon ◽  
David L. Gordon ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Factor H ◽  
Treponema Denticola ◽  
Binding Ability ◽  
Independent Manner ◽  
Complement Regulatory Proteins ◽  
Factor I ◽  
Short Consensus Repeats ◽  
Alternative Complement ◽  
Recombinant Fragments

ABSTRACT Treponema denticola is an important contributor to periodontal disease. In this study we investigated the ability of T. denticola to bind the complement regulatory proteins factor H and factor H-like protein 1 (FHL-1). The binding of these proteins has been demonstrated to facilitate evasion of the alternative complement cascade and/or to play a role in adherence and invasion. Here we demonstrate that T. denticola specifically binds FHL-1 via a 14-kDa, surface-exposed protein that we designated FhbB. Consistent with its FHL-1 binding specificity, FhbB binds only to factor H recombinant fragments spanning short consensus repeats (SCRs) 1 to 7 (H7 construct) and not to SCR constructs spanning SCRs 8 to 15 and 16 to 20. Binding of H7 to FhbB was inhibited by heparin. The specific involvement of SCR 7 in the interaction was demonstrated using an H7 mutant (H7AB) in which specific charged residues in SCR 7 were replaced by alanine. This construct lost FhbB binding ability. Analyses of the ability of FHL-1 bound to the surface of T. denticola to serve as a cofactor for factor I-mediated cleavage of C3b revealed that C3b is cleaved in an FHL-1/factor I-independent manner, perhaps by an unidentified protease. Based on the data presented here, we hypothesize that the primary function of FHL-1 binding by T. denticola might be to facilitate adherence to FHL-1 present on anchorage-dependent cells and in the extracellular matrix.

scholarly journals Impact of the SpeB Protease on Binding of the Complement Regulatory Proteins Factor H and Factor H-Like Protein 1 by Streptococcus pyogenes

2005 ◽  
Vol 73 (4) ◽  
pp. 2040-2050 ◽  
Author(s):  
Lin Wei ◽  
Vinod Pandiripally ◽  
Eugene Gregory ◽  
Micaya Clymer ◽  
David Cue
Keyword(s):  
Binding Site ◽  
Streptococcus Pyogenes ◽  
Dna Sequences ◽  
Factor H ◽  
Regulatory Proteins ◽  
Microbial Pathogens ◽  
Complement Regulatory Proteins ◽  
Human Pathogenic Bacterium ◽  
Binding Factor ◽  
Intracellular Invasion

ABSTRACT Microbial pathogens often exploit human complement regulatory proteins such as factor H (FH) and factor H-like protein 1 (FHL-1) for immune evasion. Fba is an FH and FHL-1 binding protein expressed on the surface of the human pathogenic bacterium Streptococcus pyogenes, a common agent of pharyngeal, skin, and soft-tissue infections. Fba has been shown to contribute to phagocytosis resistance, intracellular invasion, and virulence in mice. Here, we look at the role of Fba in recruitment of FH and FHL-1 by five serotype M1 isolates of streptococci. Inactivation of fba greatly inhibited binding of FH and FHL-1 by all isolates, indicating that Fba is a major FH and FHL-1 binding factor of serotype M1 streptococci. For three isolates, FH binding was significantly reduced in stationary-phase cultures and correlated with high levels of protease activity and SpeB (an extracellular cysteine protease) protein in culture supernatants. Analysis of a speB mutant confirmed that SpeB accounts for the loss of Fba from the cell surface, suggesting that the protease may modulate FH and FHL-1 recruitment during infection. Comparisons of fba DNA sequences revealed that the FH and FHL-1 binding site in Fba is conserved among the M1 isolates. Although the ligand binding site is not strictly conserved in Fba from a serotype M49 isolate, the M49 Fba protein was found to bind both FH and FHL-1. Collectively, these data indicate that binding of FH and FHL-1 is a conserved function of Fba while modulation of Fba function by SpeB is variable.

scholarly journals Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1267-1279 ◽  
Author(s):  
Jessica Caprioli ◽  
Marina Noris ◽  
Simona Brioschi ◽  
Gaia Pianetti ◽  
Federica Castelletti ◽  
...  
Keyword(s):  
Disease Recurrence ◽  
Factor H ◽  
Response To Therapy ◽  
Regulatory Proteins ◽  
Response To Treatment ◽  
Complement Factor ◽  
Genetic Studies ◽  
Complement Regulatory Proteins ◽  
Uremic Syndrome ◽  
The Impact

Abstract Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non–Shiga toxin–associated HUS (non-Stx–HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx–HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCP-mutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments.

scholarly journals Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion

2016 ◽  
Vol 7 ◽  
Author(s):  
Elise S. Hovingh ◽  
Bryan van den Broek ◽  
Ilse Jongerius
Keyword(s):  
Immune Evasion ◽  
Regulatory Proteins ◽  
Complement Regulatory Proteins

scholarly journals Identification and Functional Characterization of Complement Regulator-Acquiring Surface Protein 1 of the Lyme Disease Spirochetes Borrelia afzelii and Borrelia garinii

2005 ◽  
Vol 73 (4) ◽  
pp. 2351-2359 ◽  
Author(s):  
Reinhard Wallich ◽  
Joseph Pattathu ◽  
Veronique Kitiratschky ◽  
Christiane Brenner ◽  
Peter F. Zipfel ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Binding Site ◽  
Binding Protein ◽  
Functional Characterization ◽  
Surface Protein ◽  
Factor H ◽  
Borrelia Garinii ◽  
Borrelia Afzelii ◽  
Complement Regulator

ABSTRACT Complement regulator-acquiring surface protein 1 (CRASP-1) is the dominant factor-H-like protein 1 (FHL-1)- and factor-H-binding protein of Borrelia burgdorferi and is suggested to contribute to persistence of the pathogen. The prototype CRASP-1 of B. burgdorferi sensu stricto (CRASP-1Bb) has been formerly characterized. As shown recently, serum-resistant Borrelia afzelii strains express a unique FHL-1 and factor H-binding protein, designated CRASP-1Ba. Here, we describe for the first time the isolation and functional characterization of the gene encoding the full-length CRASP-1Ba of 28 kDa, which, upon processing, is predicted to be 26.4 kDa. CPASP-1Ba of B. afzelii spirochetes is associated with a genetic locus encoding the orthologous gbb54 gene family that maps to the linear plasmid of approximately 54 kb. Ligand affinity blotting techniques demonstrate that both native and recombinant CRASP-1Ba molecules strongly bind to FHL-1 and much more weakly to factor H. The FHL-1 and factor-H-binding site in CRASP-1Ba is shown to be localized to a 12-amino-acid residue domain at the C terminus of the protein. For comparison, the corresponding cspA-like gene(s) of a serum-sensitive Borrelia garinii strain has also been cloned and characterized. Most notably, two CRASP-1-related B. garinii proteins were identified; however, both molecules bind only weakly to FHL-1 and not at all to factor H. The present identification of the binding site of CRASP-1Ba represents an important step forward in our understanding of the pathogenesis of Lyme disease and may be helpful to design therapeutic regimens to interfere with complement evasion strategies of human pathogenic Borrelia strains.

scholarly journals An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD)

2010 ◽  
Vol 19 (23) ◽  
pp. 4694-4704 ◽  
Author(s):  
Lars G. Fritsche ◽  
Nadine Lauer ◽  
Andrea Hartmann ◽  
Selina Stippa ◽  
Claudia N. Keilhauer ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Regulatory Proteins ◽  
Human Complement ◽  
Complement Regulatory Proteins ◽  
Age Related
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