Disease-associated sequence variations congregate in a polyanion-recognition patch on human factor H revealed in 3D structure.

AP Herbert, D Uhrin, M Lyon, MK Pangburn, PN. Barlow

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Mutations and polymorphisms in the regulator of complement activation, factor H, have been linked to atypical hemolytic uremic syndrome (aHUS), membranoproliferative glomerulonephritis, and age-related macular degeneration. Many aHUS patients carry mutations in the two C-terminal modules of factor H, which normally confer upon this abundant 155 kDa plasma glycoprotein its ability to selectively bind self-surfaces and prevent them from inappropriately triggering the complement cascade via the alternative pathway. In the current study, the three-dimensional solution structure of the C-terminal module-pair of factor H has been determined. A binding site for a fully sulfated heparin-derived tetrasaccharide has been delineated using chemical shift mapping, and the C3d/C3b-binding site inferred from sequence comparisons and computational docking. The resultant information allows assessment of the likely consequences of aHUS-associated amino acid substitutions in this critical region of factor H. It is striking that, excepting those likely to perturb the 3D-structure, aHUS-associated missense mutations congregate in the polyanion-binding site delineated in this study, thus potentially disrupting a vital mechanism for control of complement on self-surfaces in the microvasculature of the kidney. It is intriguing that an SNP predisposing to age-related macular degeneration occupies another region of factor H that harbours a polyanion-binding site.
    Original languageEnglish
    JournalJournal of Biological Chemistry
    Publication statusPublished - 16 Jun 2006

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