Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS

Jennifer Stine Elam, Alexander B. Taylor, Richard Strange, Svetlana Antonyuk, Peter A. Doucette, Jorge A. Rodriguez, S. Samar Hasnain, Lawrence J. Hayward, Joan Selverstone Valentine, Todd O. Yeates, P. John Hart

Producción científica: Articlerevisión exhaustiva

297 Citas (Scopus)

Resumen

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 β-sheets. Amyloid-like filaments and water-filled nanotubes arise through extensive interactions between loop and β-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 β-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 metaldeficient enzyme could be a toxic property common to mutants of SOD1 linked to FALS.

Idioma originalEnglish (US)
Páginas (desde-hasta)461-467
Número de páginas7
PublicaciónNature Structural Biology
Volumen10
N.º6
DOI
EstadoPublished - jun 1 2003

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

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