Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization.
Teilum, Kaare LU ; Smith, Melanie LU ; Schulz, Eike ; Christensen, Lea C ; Solomentsev, Gleb LU ; Oliveberg, Mikael and Akke, Mikael LU
(2009)
In Proceedings of the National Academy of Sciences
106(43).
p.18273-18278
- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1500342
- author
- Teilum, Kaare
LU
; Smith, Melanie
LU
; Schulz, Eike
; Christensen, Lea C
; Solomentsev, Gleb
LU
; Oliveberg, Mikael
and Akke, Mikael
LU
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Proceedings of the National Academy of Sciences
- volume
- 106
- issue
- 43
- pages
- 18273 - 18278
- publisher
- National Academy of Sciences
- external identifiers
-
- wos:000271222500043
- pmid:19828437
- scopus:70849113863
- pmid:19828437
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.0907387106
- language
- English
- LU publication?
- yes
- id
- 22eeba98-b7ec-4426-8b9d-514c6ce8e598 (old id 1500342)
- date added to LUP
- 2016-04-01 12:21:05
- date last changed
- 2022-03-13 08:45:01
@article{22eeba98-b7ec-4426-8b9d-514c6ce8e598,
abstract = {{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.}},
author = {{Teilum, Kaare and Smith, Melanie and Schulz, Eike and Christensen, Lea C and Solomentsev, Gleb and Oliveberg, Mikael and Akke, Mikael}},
issn = {{1091-6490}},
language = {{eng}},
number = {{43}},
pages = {{18273--18278}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences}},
title = {{Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization.}},
url = {{http://dx.doi.org/10.1073/pnas.0907387106}},
doi = {{10.1073/pnas.0907387106}},
volume = {{106}},
year = {{2009}},
}