Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure.
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.
Edinburgh Biomolecular NMR Unit, University of Edinburgh, West mains Road, Edinburgh EH9 3JJ, United Kingdom.
Andrew P
AP
Herbert
Dusan
D
Uhrín
Malcolm
M
Lyon
Michael K
MK
Pangburn
Paul N
PN
Barlow
D000595:Amino Acid Sequence; D000838:Anions / Q000737:chemistry*; D015933:Complement C3d / Q000737:chemistry; D017242:Complement Factor H / Q000737:chemistry*; D006493:Heparin / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008969:Molecular Sequence Data; D010843:Pichia / Q000378:metabolism; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D000838:Anions; D015933:Complement C3d; D017242:Complement Factor H; D006493:Heparin