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Publication Detail
Molecular modelling of the C-terminal domains of factor H of human complement: a correlation between haemolytic uraemic syndrome and a predicted heparin binding site.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Perkins SJ, Goodship THJ
  • Publication date:
  • Pagination:
    217, 224
  • Journal:
    J Mol Biol
  • Volume:
  • Issue:
  • Status:
  • Country:
  • Print ISSN:
  • PII:
  • Language:
  • Keywords:
    Amino Acid Sequence, Animals, Binding Sites, Complement Factor H, Crystallography, X-Ray, Hemolytic-Uremic Syndrome, Heparin, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Protein Structure, Tertiary, Repetitive Sequences, Amino Acid, Sequence Alignment, Structure-Activity Relationship
Factor H (FH) of the complement system acts as a regulatory cofactor for the factor I-mediated cleavage of C3b and binds to polyanionic substrates. FH is composed of 20 short consensus/complement repeat (SCR) domains. A set of 12 missense mutations in the C-terminal domains between SCR-16 to SCR-20 is associated with haemolytic uraemic syndrome. Recent structural models for intact FH permit the molecular interpretation of these amino acid substitutions. As all nine SCR-20 substitutions correspond to normal amounts of FH in plasma, and were localised in mostly surface-exposed positions, these are inferred to lead to a functional defect in FH. The nine substitutions occur in the same spatial region of SCR-20. As this surface coincides with conserved basic residues in the C-terminal SCR-20 domain, the substitutions provide direct evidence for a polyanionic binding surface. The positions of these conserved basic residues coincide with those of heparin-binding residues in the crystal structure of the acidic fibroblast growth factor-heparin complex. A tenth substitution and another conserved basic residue in SCR-19 are proximate to this binding site. As the remaining FH substitutions could also be correlated with their proximity to conserved basic residues, haemolytic uraemic syndrome may result from a failure of FH to interact with polyanions at cell surfaces in the kidney.
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