Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization

Research output: Contribution to journalJournal articleResearchpeer-review

Kaare Teilum, Melanie H Smith, Eike Schulz, Lea C Christensen, Gleb Solomentsev, Mikael Oliveberg, Mikael Akke

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 languageEnglish
JournalProceedings of the National Academy of Science of the United States of America
Volume106
Issue number43
Pages (from-to)18273-8
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 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