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Complement factor H binds to denatured rather than to native pentameric C-reactive protein

Hakobyan, Svetlana, Harris, Claire Louise, Van Den Berg, Carmen Wilma, Fernandez-Alonso, Maria Carmen, de Jorge, Elena Goicoechea, de Cordoba, Santiago Rodriguez, Rivas, German, Mangione, Palma, Pepys, Mark B. and Morgan, Bryan Paul ORCID: 2008. Complement factor H binds to denatured rather than to native pentameric C-reactive protein. Journal of Biological Chemistry 283 (45) , pp. 30451-30460. 10.1074/jbc.M803648200

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Binding of the complement regulatory protein, factor H, to C-reactive protein has been reported and implicated as the biological basis for association of the H402 polymorphic variant of factor H with macular degeneration. Published studies utilize solid-phase or fluid-phase binding assays to show that the factor H Y402 variant binds C-reactive protein more strongly than H402. Diminished binding of H402 variant to C-reactive protein in retinal drusen is posited to permit increased complement activation, driving inflammation and pathology. We used well validated native human C-reactive protein and pure factor H Y402H variants to test interactions. When factor H variants were incubated with C-reactive protein in the fluid phase at physiological concentrations, no association occurred. When C-reactive protein was immobilized on plastic, either non-specifically by adsorption in the presence of Ca2+ to maintain its native fold and pentameric subunit assembly or by specific Ca2+-dependent binding to immobilized natural ligands, no specific binding of either factor H variant from the fluid phase was observed. In contrast, both factor H variants reproducibly bound to C-reactive protein immobilized in the absence of Ca2+, conditions that destabilize the native fold and pentameric assembly. Both factor H variants strongly bound C-reactive protein that was denatured by heat treatment before immobilization, confirming interaction with denatured but not native C-reactive protein. We conclude that the reported binding of factor H to C-reactive protein results from denaturation of the C-reactive protein during immobilization. Differential binding to C-reactive protein, thus, does not explain association of the Y402H polymorphism with macular degeneration.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RZ Other systems of medicine
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Funders: Wellcome Trust Programme Grant 068590, Wellcome Trust University Award 068823, Spanish Ministerio de Educacion y Cultura Grant SAF2005-00913
Last Modified: 06 Oct 2023 06:19

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