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A structural modeling approach for the understanding of initiation and elongation of ALS-linked superoxide dismutase fibrils

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Abstract

Familial amyotrophic lateral sclerosis caused by mutations in copper-zinc superoxide dismutase (SOD1) is characterized by the presence of SOD1-rich inclusions in spinal cords. It has been shown that a reduced intra-subunit disulfide bridge apo-SOD1 can rapidly initiate fibrillation forming an inter-subunits disulfide under mild, physiologically accessible conditions. Once initiated, elongation can proceed via recruitment of either apo or partially metallated disulfide-intact SOD1 and the presence of copper, but not zinc, ions inhibit fibrillation. We propose a structural model, refined through molecular dynamics simulations, that, taking into account these experimental findings, provides a molecular explanation for the initiation and the elongation of SOD1 fibrils in physiological conditions. The model indicates the occurrence of a new dimeric unit, prone to interact one with the other due to the presence of a wide hydrophobic surface and specific electrostatic interactions. The model has dimensions consistent with the SOD1 fibril size observed through electron microscopy and provides a structural basis for the understanding of SOD1 fibrillation.

ALS-linked superoxide dismutase fibrils

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Authors and Affiliations

  1. Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica, 00133, Rome, Italy

    Mattia Falconi, Federico Iacovelli & Alessandro Desideri

  2. Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), Rome, Italy

    Mattia Falconi, Federico Iacovelli & Alessandro Desideri

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  1. Mattia Falconi
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  2. Federico Iacovelli
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  3. Alessandro Desideri
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Correspondence to Mattia Falconi.

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Falconi, M., Iacovelli, F. & Desideri, A. A structural modeling approach for the understanding of initiation and elongation of ALS-linked superoxide dismutase fibrils. J Mol Model 19, 3695–3704 (2013). https://doi.org/10.1007/s00894-013-1896-7

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