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

Nature Structural & Molecular Biology volume 10, pages 461–467 (2003)Cite this article

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 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 metal-deficient enzyme could be a toxic property common to mutants of SOD1 linked to FALS.

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Figure 1: Disorder and conformational changes in pathogenic SOD1 molecules leading to GOI interfaces and filamentous assembly.
Figure 2: GOI interfaces in pathogenic SOD1 give rise to cross-β fibrils in two different crystal systems.
Figure 3: Two orthogonal views of apo H46R filament 2, represented by three SOD1 dimers in the same orientation as in Fig. 2a.
Figure 4: Gain-of-interaction in Zn–H46R SOD1 giving rise to water-filled helical filaments.

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Acknowledgements

We thank L. Flaks, and J. Berendzen for support at beamline X8-C at the NSLS, Brookhaven National Laboratory; D. Cascio and M. Hough for their interest and valuable discussions; S. Holloway for assistance with the illustrations and our colleagues who have offered comments during the preparation of this manuscript. This work was supported by the National Institutes of Health (L.J.H., J.S.V. and P.J.H.), the Robert A. Welch Foundation (P.J.H.), the ALS Association (L.J.H., J.S.V and P.J.H.), the MND Association (S.S.H.) and a predoctoral fellowship from the Association for the Advancement of Aging Research (J.S.E.). Funding from CCLRC and resources at Daresbury are also gratefully acknowledged.

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Authors and Affiliations

  1. 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, 78229-3900, Texas, USA

    Jennifer Stine Elam, Alexander B Taylor & P John Hart

  2. Department of Synchrotron Radiation, Molecular Biophysics Group, CCLRC Daresbury Laboratory, Warrington, WA44AD, Cheshire, UK

    Richard Strange, Svetlana Antonyuk & S Samar Hasnain

  3. Department of Chemistry and Biochemistry, University of California, Los Angeles, 90095, California, USA

    Peter A Doucette, Jorge A Rodriguez, Joan Selverstone Valentine & Todd O Yeates

  4. Department of Neurology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655, Massachusetts, USA

    Lawrence J Hayward

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Elam, J., Taylor, A., Strange, R. et al. Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS. Nat Struct Mol Biol 10, 461–467 (2003). https://doi.org/10.1038/nsb935

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