title: 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.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, University College London, Rowland Hill Street, London, NW3 2PF, UK. s.perkins@rfc.ucl.ac.uk
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Perkins
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017242:Complement Factor H / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: C493495:CFH protein, human; D017242:Complement Factor H; D006493:Heparin