Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure.
Affiliation
Edinburgh Biomolecular NMR Unit, University of Edinburgh, West mains Road, Edinburgh EH9 3JJ, United Kingdom.Issue Date
2006-06-16
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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 three-dimensional 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 a single nucleotide polymorphism predisposing to age-related macular degeneration occupies another region of factor H that harbors a polyanion-binding site.Citation
Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure. 2006, 281 (24):16512-20 J. Biol. Chem.Journal
The Journal of Biological ChemistryDOI
10.1074/jbc.M513611200PubMed ID
16533809Type
ArticleLanguage
enISSN
0021-9258ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M513611200
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