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 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.
Highlights
Hemolytic uremic syndrome is a thrombotic microangiopathy that occurs primarily in the kidneys
We describe the structure of a region of factor H implicated in atypical hemolytic uremic syndrome (HUS)
Between 10 and 30% of atypical variant of HUS (aHUS) patients are heterozygous for mutations in the complement regulatory protein, factor H [4, 5], most of which map to its C-terminal region [15,16,17]
Summary
Cofactor for proteolytic cleavage of C3b, and accelerates the decay of the C3 convertase into its components [22, 23]. The cofactor and decay acceleration activities of fH map to the N-terminal four CCPs [24, 25]. It is noteworthy that the two C-terminal modules of fH harbor a binding site for polyanions and one for C3b/C3d, in addition to being a hotspot of aHUS-associated mutations [15]. This polyanionbinding site appears to represent a site for attachment to endothelial cell surfaces [33]. As described below, elucidation of the three-dimensional structure of the CCPs 19 and 20 (fHϳ19 –20) and experimental identification of the residues that comprise a polyanion recognition site represent a powerful means of investigating these hypotheses further
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