Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization
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Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization. / Teilum, Kaare; Smith, Melanie H; Schulz, Eike; Christensen, Lea C; Solomentsev, Gleb; Oliveberg, Mikael; Akke, Mikael.
in: P NATL ACAD SCI USA, Jahrgang 106, Nr. 43, 27.10.2009, S. 18273-18278.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization
AU - Teilum, Kaare
AU - Smith, Melanie H
AU - Schulz, Eike
AU - Christensen, Lea C
AU - Solomentsev, Gleb
AU - Oliveberg, Mikael
AU - Akke, Mikael
PY - 2009/10/27
Y1 - 2009/10/27
N2 - 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.
AB - 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.
KW - Apoenzymes/chemistry
KW - Disulfides/chemistry
KW - Humans
KW - Models, Molecular
KW - Mutation
KW - Nuclear Magnetic Resonance, Biomolecular
KW - Protein Multimerization
KW - Protein Structure, Quaternary
KW - Protein Structure, Tertiary
KW - Superoxide Dismutase/chemistry
KW - Superoxide Dismutase-1
U2 - 10.1073/pnas.0907387106
DO - 10.1073/pnas.0907387106
M3 - SCORING: Journal article
C2 - 19828437
VL - 106
SP - 18273
EP - 18278
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 43
ER -