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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

Lookup NU author(s): Professor Tim Goodship


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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. © 2002 Elsevier Science Ltd.

Publication metadata

Author(s): Goodship THJ; Perkins SJ

Publication type: Article

Publication status: Published

Journal: Journal of Molecular Biology

Year: 2002

Volume: 316

Issue: 2

Pages: 217-224

ISSN (print): 0022-2836

ISSN (electronic):

Publisher: Academic Press


DOI: 10.1006/jmbi.2001.5337

PubMed id: 11851332


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