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Zinc-induced self-association of complement C3b and Factor H: implications for inflammation and age-related macular degeneration.

Nan, R; Tetchner, S; Rodriguez, E; Pao, PJ; Gor, J; Lengyel, I; Perkins, SJ; (2013) Zinc-induced self-association of complement C3b and Factor H: implications for inflammation and age-related macular degeneration. Journal of Biological Chemistry 10.1074/jbc.M113.476143. Green open access

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Abstract

The sub-retinal pigment epithelial deposits (sRPEds) that are a hallmark of age-related macular degeneration (AMD) contain both C3b and mM levels of zinc. C3 is the central protein of complement, while C3u is formed by the spontaneous hydrolysis of the thioester bridge in C3. During activation, C3 is cleaved to form active C3b, then C3b is inactivated by Factor I and Factor H to form the C3c and C3d fragments. The interaction of zinc with C3 was quantified using analytical ultracentrifugation and X-ray scattering. C3, C3u, and C3b associated strongly in >100 μM [Zn], while C3c and C3d showed weak association. With zinc, C3 forms soluble oligomers, while C3u and C3b precipitate. We conclude that the C3, C3u and C3b association with zinc depended on the relative positions of C3d and C3c in each protein. Computational predictions showed that putative weak zinc binding sites with different capacities exist in all five proteins, in agreement with experiment. Factor H forms large oligomers in >10 μM [Zn]. In distinction to C3b or Factor H alone, the solubility of the central C3b-Factor H complex was much reduced at 60 μM [Zn], and even more so at >100 μM [Zn]. The removal of the C3b-Factor H complex by zinc explains the reduced C3u/C3b inactivation rates by zinc. Zinc-induced precipitation may contribute to the initial development of sRPEds in the retina, as well as reducing the progression to advanced AMD in higher-risk patients.

Type: Article
Title: Zinc-induced self-association of complement C3b and Factor H: implications for inflammation and age-related macular degeneration.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M113.476143
Publisher version: http://dx.doi.org/10.1074/jbc.M113.476143
Language: English
Additional information: © 2013. This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Age-related macular degeneration, Analytical ultracentrifugation, Complement, Inflammation, X-ray scattering, Zinc
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1393825
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