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Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization.
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2009 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 1091-6490, Vol. 106, no 43, 18273-8 p.Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to the misfolding of Cu/Zn superoxide dismutase (SOD1). ALS-related defects in SOD1 result in a gain of toxic function that coincides with aberrant oligomerization. The structural events triggering oligomerization have remained enigmatic, however, as is the case in other protein-misfolding diseases. Here, we target the critical conformational change that defines the earliest step toward aggregation. Using nuclear spin relaxation dispersion experiments, we identified a short-lived (0.4 ms) and weakly populated (0.7%) conformation of metal-depleted SOD1 that triggers aberrant oligomerization. This excited state emanates from the folded ground state and is suppressed by metal binding, but is present in both the disulfide-oxidized and disulfide-reduced forms of the protein. Our results pinpoint a perturbed region of the excited-state structure that forms intermolecular contacts in the earliest nonnative dimer/oligomer. The conformational transition that triggers oligomerization is a common feature of WT SOD1 and ALS-associated mutants that have widely different physicochemical properties. But compared with WT SOD1, the mutants have enhanced structural distortions in their excited states, and in some cases slightly higher excited-state populations and lower kinetic barriers, implying increased susceptibility to oligomerization. Our results provide a unified picture that highlights both (i) a common denominator among different SOD1 variants that may explain why diverse mutations cause the same disease, and (ii) a structural basis that may aid in understanding how different mutations affect disease propensity and progression.

Place, publisher, year, edition, pages
2009. Vol. 106, no 43, 18273-8 p.
URN: urn:nbn:se:su:diva-34565DOI: 10.1073/pnas.0907387106ISI: 000271222500043PubMedID: 19828437OAI: diva2:285130
Available from: 2010-01-11 Created: 2010-01-11 Last updated: 2010-11-26Bibliographically approved

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Oliveberg, Mikael
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Department of Biochemistry and Biophysics

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