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Multiple Interactions of Complement Factor H with Its Ligands in Solution: A Progress Report

  • Stephen J. Perkins
  • Ruodan Nan
  • Azubuike I. Okemefuna
  • Keying Li
  • Sanaullah Khan
  • Ami Miller
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 703)

Abstract

Factor H (FH) is the major regulator of the central complement protein C3b in the alternative pathway of complement activation, and is comprised of 20 SCR domains. A FH Tyr402His polymorphism in SCR-7 is associated with age-related macular degeneration (AMD) and leads to deposition of complement in drusen. The unravelling of how FH interacts with five major physiological and patho-physiological ligands is complicated by the weak nature of these interactions, coupled with the multivalency of FH. Using multiple biophysical methods, we summarise our recent results for these five FH ligands: (1) FH by itself shows a folded-back SCR domain structure in solution, and self-associates in a manner dependent on electrostatic forces. (2) FH activity is inhibited by zinc, which causes FH to aggregate. The onset of FH-zinc aggregation for zinc concentrations above 20 μM appears to be enhanced with the His402 allotype, and may be relevant to AMD. (3) The FH and C-reactive protein (CRP) interaction has been controversial; however our new work resolves earlier discrepancies. The FH-CRP interaction is only observed when native CRP is at high acute-phase concentration levels, and CRP binds weakly to the His402 FH allotype to suggest a molecular mechanism that leads to AMD. (4) Heparin is an analogue of the polyanionic host cell surface, and FH forms higher oligomers with larger heparin fragments, suggesting a mechanism for more effective FH regulation. (5) The interaction of C3b with FH also depends on buffer, and FH forms multimers with the C3d fragment of C3b. This FH-C3d interaction at high FH concentration may also facilitate complement regulation. Overall, our results to date suggest that the FH interactions involving zinc and native CRP have the closest relevance for explaining the onset of AMD.

Keywords

Surface Plasmon Resonance Retinal Pigment Epithelium Sedimentation Coefficient Analytical Ultracentrifugation Host Cell Surface 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank University College London, the Biotechnology and Biological Sciences Research Council, the Mercer Fund of the Fight For Sight Charity, the Henry Smith Charity and the Higher Education Commission of Pakistan for studentship and grant funding. We are particularly grateful to Dr Imre Lengyel and Prof Alan Bird of the UCL Institute of Ophthalmology for useful discussions in relation to AMD, and Jayesh Gor in the UCL Structural Immunology group and Dr Theyencheri Narayanan, Dr Anuj Shukla and Dr Shirley Callow at ESRF for invaluable instrumental support.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Stephen J. Perkins
    • 1
  • Ruodan Nan
  • Azubuike I. Okemefuna
  • Keying Li
  • Sanaullah Khan
  • Ami Miller
  1. 1.Department of Structural and Molecular BiologyUniversity College LondonLondonUK

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