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Lookup NU author(s): Professor David KavanaghORCiD
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Factor H (fH) is essential for complement homeostasis in fluid-phase and on surfaces. Its two C-terminal domains (CCP 19-20) anchor fH to self-surfaces where it prevents C3b amplification in a process requiring its N-terminal four domains. In atypical hemolytic uremic syndrome (aHUS), mutations clustering toward the C terminus of fH may disrupt interactions with surface-associated C3b or polyanions and thereby diminish the ability of fH to regulate complement. To test this, we compared a recombinant protein encompassing CCP 19-20 with 16 mutants. The mutations had only very limited and localized effects on protein structure. Although we found four aHUS-linked fH mutations that decreased binding to C3b and/or to heparin (a model compound for cell surface polyanionic carbohydrates), we identified five aHUS-associated mutants with increased affinity for either or both ligands. Strikingly, these variable affinities for the individual ligands did not correlate with the extent to which all the aHUS-associated mutants were found to be impaired in a more physiological assay that measured their ability to inhibit cell surface complement functions of full-length fH. Taken together, our data suggest that disruption of a complex fH-self-surface recognition process, involving a balance of affinities for protein and physiological carbohydrate ligands, predisposes to aHUS.
Author(s): Ferreira VP, Herbert AP, Cortés C, McKee KA, Blaum BS, Esswein ST, Uhrín D, Barlow PN, Pangburn MK, Kavanagh D
Publication type: Article
Publication status: Published
Journal: Journal of Immunology
ISSN (print): 0022-1767
ISSN (electronic): 1550-6606
Publisher: American Association of Immunologists
Notes: 078780/Z/05/Z/Wellcome Trust/United Kingdom
DK-35081/DK/NIDDK NIH HHS/United States
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
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