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Related Experiment Videos

Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in

Andrew P Herbert1, Dusan Uhrín, Malcolm Lyon

  • 1Edinburgh Biomolecular NMR Unit, University of Edinburgh, West mains Road, Edinburgh EH9 3JJ, United Kingdom.

The Journal of Biological Chemistry
|March 15, 2006
PubMed
Summary

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Mutations in factor H, a complement regulator, are linked to kidney disease. This study reveals how aHUS mutations disrupt factor H

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Immunology

Background:

  • Factor H is a key regulator of the alternative complement pathway.
  • Mutations in factor H are associated with diseases like atypical hemolytic uremic syndrome (aHUS).
  • The C-terminal modules of factor H are crucial for its self-surface recognition and regulation.

Purpose of the Study:

  • To determine the three-dimensional solution structure of the C-terminal module pair of factor H.
  • To identify and characterize the binding sites within the C-terminal modules of factor H.
  • To assess the impact of aHUS-associated mutations on factor H function.

Main Methods:

  • Three-dimensional structure determination using solution techniques.
  • Chemical shift mapping to delineate heparin-binding sites.

Related Experiment Videos

  • Sequence comparisons and computational docking to infer C3d/C3b-binding sites.

    • Main Results:

    • The three-dimensional structure of the C-terminal module pair of factor H was determined.
    • A binding site for a heparin-derived tetrasaccharide was identified.
    • The C3d/C3b-binding site was inferred, revealing its location relative to the polyanion-binding site.
    • Atypical hemolytic uremic syndrome-associated missense mutations cluster in the identified polyanion-binding site.

    Conclusions:

    • The study elucidates the structural basis for factor H's interaction with self-surfaces.
    • The findings suggest that aHUS-associated mutations disrupt complement regulation by impairing polyanion binding.
    • This provides a molecular understanding of how factor H dysfunction leads to kidney disease.