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Publication Detail
Uncontrolled Zinc- and Copper-Induced Oligomerisation of the Human Complement Regulator Factor H and Its Possible Implications for Function and Disease
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Nan R, Gor J, Lengyel I, Perkins SJ
  • Publication date:
  • Pagination:
    1341, 1352
  • Journal:
    Journal of Molecular Biology
  • Volume:
  • Issue:
  • Print ISSN:
  • Addresses:
    Institute of Structural and Molecular Biology, Division of Biosciences, Darwin Building, University College London, Gower Street, London WC1E 6BT, UK
  • Notes:
    DA - 20081205IS - 1089-8638 (Electronic)LA - ENGPT - JOURNAL ARTICLE
Polymorphisms in factor H (FH), a major regulator of complement activation, and the accumulation of high zinc concentrations in the outer retina are both associated with age-related macular degeneration. FH is inhibited by zinc, which causes FH to aggregate. To investigate this, we quantitatively studied zinc-induced FH self-association by X-ray scattering and analytical ultracentrifugation to demonstrate uncontrolled FH oligomerisation in conditions corresponding to physiological levels of FH and pathological levels of zinc in the outer retina. By scattering, FH at 2.8-7.0 muM was unaffected until [Zn] increased to 20 muM, whereupon the radius of gyration, R(G), values increased from 9 to 15 nm at [Zn]=200 muM. The maximum dimension of FH increased from 32 to 50 nm, indicating that compact oligomers had formed. By ultracentrifugation, size-distribution analyses showed that monomeric FH at 5.57 S was the major species at [Zn] up to 60 muM. At [Zn] above 60 muM, a series of large oligomers were formed, ranging up to 100 S in size. Oligomerisation was reversed by ethylenediaminetetraacetic acid. Structurally distinct large oligomers were observed for Cu, while Ni, Cd and Fe showed low amounts of oligomers and Mg and Ca showed no change. Fluid-phase assays showed reduced FH activities that correlated with increased oligomer formation. The results were attributed to different degrees of stabilisation of weak self-dimerisation sites in FH by transition metals. The relevance of metal-induced FH oligomer formation to complement regulation and age-related macular degeneration is discussed
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