Dimerization of complement factor H-related proteins modulates complement activation in vivo

Elena Goicoechea de Jorge1, Joseph J. E. Caesar2, Talat H. Malik3, Mitali Patel3, Matthew Colledge2, Steven Johnson2, Svetlana Hakobyan4, B. Paul Morgan4, Claire L. Harris4, Matthew C. Pickering3, Susan M. Lea2
1Centre for Complement and Inflammation Research, Department of Medicine, Imperial College, London W12 0NN, United Kingdom.
2Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; and
3aCentre for Complement and Inflammation Research, Department of Medicine, Imperial College, London W12 0NN, United Kingdom;
4Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4YU, United Kingdom

Tóm tắt

The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related ( CFHR ) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

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