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

J Mol Biol. 2002 Feb 15;316(2):217-24. doi: 10.1006/jmbi.2001.5337.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Complement Factor H / chemistry*
  • Complement Factor H / genetics
  • Complement Factor H / metabolism*
  • Crystallography, X-Ray
  • Hemolytic-Uremic Syndrome / genetics*
  • Heparin / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense / genetics
  • Protein Structure, Tertiary
  • Repetitive Sequences, Amino Acid / genetics
  • Sequence Alignment
  • Structure-Activity Relationship

Substances

  • complement factor H, human
  • Complement Factor H
  • Heparin