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I. Lengyel, R. Nan, J. Gor, S. J. Perkins; Zinc-Induced Self-Association of Complement Factor H and Its Implications for Amd. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5168.
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Complement Factor H (CFH), a major regulator of complement alternative pathway, is a genetic risk factor for age-related macular degeneration (AMD). CFH exists predominantly as a soluble monomer in a reversible equilibrium with a dimer at physiological concentrations (Nan et al. (2008) J. Mol. Biol., in press). Sub-RPE deposits and the Bruch’s membrane in post-mortem human tissues contain unexpectedly high concentrations of zinc, especially in the maculae of eyes with AMD (Lengyel et al. (2007) Exp. Eye Research, 84, 772-780). We hypothesized that the availability of high zinc concentrations in AMD affect the oligomeric properties of CFH and lead to the precipitation and deposition of CFH and the development of inflammation.
CFH was purified from outdated human plasma. Oligomerisation was monitored by X-ray scattering and analytical ultracentrifugation.
Titrations using X-ray scattering shows that 2-6 µM CFH forms large oligomers at zinc concentrations of ~6 µM and above, and precipitates at the highest zinc and CFH concentrations used. Size-distribution analyses by analytical ultracentrifugation showed that supra-large oligomers of CFH were continuously formed, starting at 0.2 µM zinc with sedimentation coefficients that correspond to low oligomers, and extending to very high oligomers at 200 µM zinc that corresponded to CFH molecular weights in excess of 1000 kDa. Monomeric CFH species were depleted at the highest CFH and zinc concentrations used. These observations are explained by the presence of at least two zinc-binding sites per monomer, each of which is able to cross-link with sites on neighboring CFH molecules, and leading to the indefinite oligomerisation of CFH.
These observations suggest that there is a link between high zinc levels and CFH aggregation and deposition into sub-RPE deposits and Bruch’s membrane. The inhibition of CFH through zinc-induced oligomerisation might be an underlying cause of the uncontrolled inflammation associated with AMD.
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