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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

Authors :
Perkins, Stephen J.
Goodship, Timothy H. J.
Source :
Journal of Molecular Biology. Feb2002, Vol. 316 Issue 2, p217. 8p.
Publication Year :
2002

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. [Copyright &y& Elsevier]

Details

Language :
English
ISSN :
00222836
Volume :
316
Issue :
2
Database :
Academic Search Index
Journal :
Journal of Molecular Biology
Publication Type :
Academic Journal
Accession number :
8497358
Full Text :
https://doi.org/10.1006/jmbi.2001.5337