title: A structural modeling approach for the understanding of initiation and elongation of ALS-linked superoxide dismutase fibrils.
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.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133, Rome, Italy. falconi@uniroma2.it
authors.forename: Mattia
authors.initials: M
authors.lastname: Falconi
authors.forename: Federico
authors.initials: F
authors.lastname: Iacovelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D004220:Disulfides; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D055503:Protein Multimerization; D021122:Protein Subunits / Q000737:chemistry; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D004220:Disulfides; D021122:Protein Subunits; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1