W0455

Misfolded Superoxide Dismutase and ALS. P. John Hart¹, Jennifer Stine Elam¹, Alexander B. Taylor¹, Richard Strange², Svetlana Antonyuk², Pete Doucette³, S. Samar Hasnain², Lawrence J. Hayward⁴, Joan Selverstone Valentine³, Todd O. Yeates^{3 1}Univ. of Texas Health Science Center, San Antonio, USA; ²CLRC Daresbury, UK; ³Univ. of California, Los Angeles, USA; ⁴Univ. of Massachusetts Medical School, Worcester, USA.

Mutations in copper-zinc superoxide dismutase (SOD1) cause the autosomal dominant, neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). In spinal cord neurons of human patients and in transgenic mice expressing these proteins, high molecular weight, insoluble protein complexes (IPCs) containing FALS SOD1 are observed. Although the molecular basis for FALS has remained obscure, accumulation of SOD1 IPCs 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 mutants S134N and H46R crystallize in three different crystal forms, all of which are characterized by higher order assemblies of aligned β-sheets. Linear, amyloid-like filaments and helical, water-filled nanotubes arise through extensive interactions between loop and β-barrel elements of neighboring SOD1 molecules. In all cases, non-native conformational changes permit the gain-of-interaction between dimers that leads to formation of higher order arrays. Normal β-sheet-containing proteins avoid such self-association by preventing their edge strands from making intermolecular interactions, often by covering them with loop elements. We suggest that loss of this protection through conformational rearrangement in the metal-deficient enzyme is a toxic property that may be common to mutants of SOD1 linked to FALS.