title: Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS.
abstract: Mutations in the SOD1 gene cause the autosomal dominant, neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). In spinal cord neurons of human FALS patients and in transgenic mice expressing these mutant proteins, aggregates containing FALS SOD1 are observed. Accumulation of SOD1 aggregates is believed to interfere with axonal transport, protein degradation and anti-apoptotic functions of the neuronal cellular machinery. Here we show that metal-deficient, pathogenic SOD1 mutant proteins crystallize in three different crystal forms, all of which reveal higher-order assemblies of aligned beta-sheets. Amyloid-like filaments and water-filled nanotubes arise through extensive interactions between loop and beta-barrel elements of neighboring mutant SOD1 molecules. In all cases, non-native conformational changes permit a gain of interaction between dimers that leads to higher-order arrays. Normal beta-sheet-containing proteins avoid such self-association by preventing their edge strands from making intermolecular interactions. Loss of this protection through conformational rearrangement in the metal-deficient enzyme could be a toxic property common to mutants of SOD1 linked to FALS.
authors.affiliation: Department of Biochemistry and the Center for Biomolecular Structure Analysis, The University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900, USA.
authors.forename: Jennifer Stine
authors.initials: JS
authors.lastname: Elam
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Taylor
authors.forename: Richard
authors.initials: R
authors.lastname: Strange
authors.forename: Svetlana
authors.initials: S
authors.lastname: Antonyuk
authors.forename: Peter A
authors.initials: PA
authors.lastname: Doucette
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Rodriguez
authors.forename: S Samar
authors.initials: SS
authors.lastname: Hasnain
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Hayward
authors.forename: Joan Selverstone
authors.initials: JS
authors.lastname: Valentine
authors.forename: Todd O
authors.initials: TO
authors.lastname: Yeates
authors.forename: P John
authors.initials: PJ
authors.lastname: Hart
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D018360:Crystallography, X-Ray; D006801:Humans; D046911:Macromolecular Substances; D008670:Metals / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014867:Water / Q000737:chemistry
chemical_list: D000682:Amyloid; D046911:Macromolecular Substances; D008670:Metals; C000606290:SOD1 protein, human; D014867:Water; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1