Complement control protein factor H: The good, the bad, and the inadequate

Two mouse monoclonal antibodies against the human complement control protein, Factor H (β1H), are described. The antibodies are both IgG − γ1 - subclasses and are directed against different epitopes on the human Factor H molecule. One of the antibodies, MRC OX 24, increases the cofactor activity of Factor H in Factor I-mediated cleavage of soluble C3b. The second antibody, MRC OX 23, which has no effect alone, reduces the increase in cofactor activity observed in the presence of the first antibody. However, MRC OX 24 inhibits the binding of 125I-labelled Factor H to surface-bound C3b (EAC3b). Again MRC OX 23 alone does not have any effect but decreases the inhibition in 125I-Labelled Factor H binding to EAC3b observed with MRC OX 24. These studies show clearly that the interaction of Factor H with soluble C3b is different to its interaction with surface-bound C3b. In an indirect immunoprecipitation system using these monoclonal antibodies, single-chain molecules of 150 000 mol. wt. are specifically precipitated from human serum and also from the sera of other primates - rhesus monkey, cynomolgus monkey, and African green monkey. There was no precipitation from sera of cow, pig, sheep, chick, or rabbit. Using a radioimmunoassay with radiolabelled monoclonal MRC OX 23, the concentration of Factor H in human plasma was determined.

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SP105ATYPICAL HEMOLYTIC UREMIC SYNDROME AND C3 GLOMERULOPATHY DUE TO MONOCLONAL ANTIBODY AGAINST COMPLEMENT CONTROL PROTEIN FACTOR H

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz103.sp105 ◽

2019 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Paraskevi Eva Andronikidis ◽

Papanikolaou Vasiliki ◽

Plavoukou Styliani ◽

Tsouka Glykeria ◽

Delibasi Sosanna ◽

...

Keyword(s):

Monoclonal Antibody ◽

Hemolytic Uremic Syndrome ◽

Factor H ◽

C3 Glomerulopathy ◽

Complement Control Protein ◽

Protein Factor ◽

Uremic Syndrome ◽

Control Protein

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Utilising ion mobility-mass spectrometry to interrogate macromolecules: Factor H complement control protein modules 10–15 and 19–20 and the DNA-binding core domain of tumour suppressor p53

International Journal of Mass Spectrometry ◽

10.1016/j.ijms.2010.01.007 ◽

2010 ◽

Vol 298 (1-3) ◽

pp. 99-110 ◽

Cited By ~ 14

Author(s):

Peter A. Faull ◽

Hannah V. Florance ◽

Christoph Q. Schmidt ◽

Nick Tomczyk ◽

Paul N. Barlow ◽

...

Keyword(s):

Mass Spectrometry ◽

Ion Mobility ◽

Factor H ◽

Ion Mobility Mass Spectrometry ◽

Core Domain ◽

Complement Control Protein ◽

Binding Core ◽

Tumour Suppressor P53 ◽

Protein Modules ◽

Control Protein

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Solution structure of the fifth repeat of factor H: a second example of the complement control protein module

Biochemistry ◽

10.1021/bi00129a011 ◽

1992 ◽

Vol 31 (14) ◽

pp. 3626-3634 ◽

Cited By ~ 80

Author(s):

P. N. Barlow ◽

D. G. Norman ◽

A. Steinkasserer ◽

T. J. Horne ◽

J. Pearce ◽

...

Keyword(s):

Solution Structure ◽

Factor H ◽

Complement Control Protein ◽

Control Protein

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Clumping Factor A Interaction with Complement Factor I Increases C3b Cleavage on the Bacterial Surface of Staphylococcus aureus and Decreases Complement-Mediated Phagocytosis

Infection and Immunity ◽

10.1128/iai.01065-09 ◽

2010 ◽

Vol 78 (4) ◽

pp. 1717-1727 ◽

Cited By ~ 65

Author(s):

Pamela S. Hair ◽

Charlene G. Echague ◽

Amber M. Sholl ◽

Justin A. Watkins ◽

Joan A. Geoghegan ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Surface Protein ◽

Factor H ◽

Complement Factor ◽

Wild Type ◽

Bacterial Surface ◽

Complement Control Protein ◽

Factor I ◽

Protein Factor ◽

Fibrinogen Binding

ABSTRACT The human complement system is important in the immunological control of Staphylococcus aureus infection. We showed previously that S. aureus surface protein clumping factor A (ClfA), when expressed in recombinant form, bound complement control protein factor I and increased factor I cleavage of C3b to iC3b. In the present study, we show that, compared to the results for the wild type, when isogenic ClfA-deficient S. aureus mutants were incubated in serum, they bound less factor I, generated less iC3b on the bacterial surface, and bound fewer C3 fragments. It has been shown previously that two amino acids in ClfA (P336 and Y338) are essential for fibrinogen binding. However, S. aureus expressing ClfA(P336A Y338S) was less virulent than ClfA-deficient strains in animal models. This suggested that ClfA contributed to S. aureus virulence by a mechanism different than fibrinogen binding. In the present study, we showed that S. aureus expressing ClfA(P336A Y338S) was more susceptible to complement-mediated phagocytosis than a ClfA-null mutant or the wild type. Unlike ClfA, ClfA(P336A Y338S) did not enhance factor I cleavage of C3b to iC3b and inhibited the cofactor function of factor H. Fibrinogen enhanced factor I binding to ClfA and the S. aureus surface. Twenty clinical S. aureus strains all expressed ClfA and bound factor I. High levels of factor I binding by clinical strains correlated with poor phagocytosis. In summary, our results suggest that the interaction of ClfA with factor I contributes to S. aureus virulence by a complement-mediated mechanism.

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Kinetic Analysis of the Interactions between Vaccinia Virus Complement Control Protein and Human Complement Proteins C3b and C4b

Journal of Virology ◽

10.1128/jvi.78.17.9446-9457.2004 ◽

2004 ◽

Vol 78 (17) ◽

pp. 9446-9457 ◽

Cited By ~ 32

Author(s):

John Bernet ◽

Jayati Mullick ◽

Yogesh Panse ◽

Pradeep B. Parab ◽

Arvind Sahu

Keyword(s):

Vaccinia Virus ◽

Binding Site ◽

Molecular Mechanisms ◽

Accurate Determination ◽

Factor H ◽

Human Complement ◽

Target Proteins ◽

Complement Control Protein ◽

Complement Proteins ◽

Control Protein

ABSTRACT The vaccinia virus complement control protein (VCP) is an immune evasion protein of vaccinia virus. Previously, VCP has been shown to bind and support inactivation of host complement proteins C3b and C4b and to protect the vaccinia virions from antibody-dependent complement-enhanced neutralization. However, the molecular mechanisms involved in the interaction of VCP with its target proteins C3b and C4b have not yet been elucidated. We have utilized surface plasmon resonance technology to study the interaction of VCP with C3b and C4b. We measured the kinetics of binding of the viral protein to its target proteins and compared it with human complement regulators factor H and sCR1, assessed the influence of immobilization of ligand on the binding kinetics, examined the effect of ionic contacts on these interactions, and sublocalized the binding site on C3b and C4b. Our results indicate that (i) the orientation of the ligand is important for accurate determination of the binding constants, as well as the mechanism of binding; (ii) in contrast to factor H and sCR1, the binding of VCP to C3b and C4b follows a simple 1:1 binding model and does not involve multiple-site interactions as predicted earlier; (iii) VCP has a 4.6-fold higher affinity for C4b than that for C3b, which is also reflected in its factor I cofactor activity; (iv) ionic interactions are important for VCP-C3b and VCP-C4b complex formation; (v) VCP does not bind simultaneously to C3b and C4b; and (vi) the binding site of VCP on C3b and C4b is located in the C3dg and C4c regions, respectively.

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