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Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):8770-8775. doi: 10.1073/pnas.1705091114. Epub 2017 Jul 31.

Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS).

Author information

1
Howard Hughes Medical Institute, UCLA-DOE and Molecular Biology Institutes, Department of Biological Chemistry, University of California, Los Angeles, CA 90095.
2
Department of Neurobiology, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
3
Department of Chemistry & Biochemistry, University of California, Los Angeles, CA 90095.
4
D. E. Shaw Research, New York, NY 10036.
5
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106.
6
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032.
7
Howard Hughes Medical Institute, UCLA-DOE and Molecular Biology Institutes, Department of Biological Chemistry, University of California, Los Angeles, CA 90095; david@mbi.ucla.edu.

Abstract

Fibrils and oligomers are the aggregated protein agents of neuronal dysfunction in ALS diseases. Whereas we now know much about fibril architecture, atomic structures of disease-related oligomers have eluded determination. Here, we determine the corkscrew-like structure of a cytotoxic segment of superoxide dismutase 1 (SOD1) in its oligomeric state. Mutations that prevent formation of this structure eliminate cytotoxicity of the segment in isolation as well as cytotoxicity of the ALS-linked mutants of SOD1 in primary motor neurons and in a Danio rerio (zebrafish) model of ALS. Cytotoxicity assays suggest that toxicity is a property of soluble oligomers, and not large insoluble aggregates. Our work adds to evidence that the toxic oligomeric entities in protein aggregation diseases contain antiparallel, out-of-register β-sheet structures and identifies a target for structure-based therapeutics in ALS.

KEYWORDS:

ALS; SOD1; oligomer

PMID:
28760994
PMCID:
PMC5565441
DOI:
10.1073/pnas.1705091114
[Indexed for MEDLINE]
Free PMC Article

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