Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Proceedings of the National Academy of Science of the United States of America |
Volume | 106 |
Issue number | 43 |
Pages (from-to) | 18273-8 |
Number of pages | 6 |
ISSN | 0027-8424 |
DOIs | |
Publication status | Published - 2009 |
Bibliographical note
Keywords: Apoenzymes; Disulfides; Humans; Models, Molecular; Mutation; Nuclear Magnetic Resonance, Biomolecular; Protein Multimerization; Protein Structure, Quaternary; Protein Structure, Tertiary; Superoxide Dismutase
ID: 18079790