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Folding Catalysis by Transient Coordination of Zn2+ to the Cu Ligands of the ALS-Associated Enzyme Cu/Zn Superoxide Dismutase 1

Leinartaite, Lina; Kadhirvel, Saraboji LU ; Nordlund, Anna; Logan, Derek LU and Oliveberg, Mikael (2010) In Journal of the American Chemical Society 132(38). p.13495-13504
Abstract
How coordination of metal ions modulates protein structures is not only important for elucidating biological function but has also emerged as a key determinant in protein turnover and protein-misfolding diseases. In this study, we show that the coordination of Zn2+ to the ALS-associated enzyme Cu/Zn superoxide dismutase (SOD1) is directly controlled by the protein's folding pathway. Zn2+ first catalyzes the folding reaction by coordinating transiently to the Cu ligands of SOD1, which are all contained within the folding nucleus. Then, after the global folding transition has commenced, the Zn2+ ion transfers to the higher affinity Zn site, which structures only very late in the folding process. Here it remains dynamically coordinated with... (More)
How coordination of metal ions modulates protein structures is not only important for elucidating biological function but has also emerged as a key determinant in protein turnover and protein-misfolding diseases. In this study, we show that the coordination of Zn2+ to the ALS-associated enzyme Cu/Zn superoxide dismutase (SOD1) is directly controlled by the protein's folding pathway. Zn2+ first catalyzes the folding reaction by coordinating transiently to the Cu ligands of SOD1, which are all contained within the folding nucleus. Then, after the global folding transition has commenced, the Zn2+ ion transfers to the higher affinity Zn site, which structures only very late in the folding process. Here it remains dynamically coordinated with an off rate of similar to 10(-5) s(-1). This relatively rapid equilibration of metals in and out of the SOD1 structure provides a simple explanation for how the exceptionally long lifetime, >100 years, of holoSOD1 is still compatible with cellular turnover: if a dissociated Zn2+ ion is prevented from rebinding to the SOD1 structure then the lifetime of the protein is reduced to a just a few hours. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of the American Chemical Society
volume
132
issue
38
pages
13495 - 13504
publisher
The American Chemical Society
external identifiers
  • wos:000282304000073
  • scopus:77957128218
ISSN
1520-5126
DOI
10.1021/ja1057136
language
English
LU publication?
yes
id
7af21991-947d-4c15-8e26-a9b918ed6fca (old id 1726991)
date added to LUP
2010-12-01 14:04:07
date last changed
2018-06-24 04:23:20
@article{7af21991-947d-4c15-8e26-a9b918ed6fca,
  abstract     = {How coordination of metal ions modulates protein structures is not only important for elucidating biological function but has also emerged as a key determinant in protein turnover and protein-misfolding diseases. In this study, we show that the coordination of Zn2+ to the ALS-associated enzyme Cu/Zn superoxide dismutase (SOD1) is directly controlled by the protein's folding pathway. Zn2+ first catalyzes the folding reaction by coordinating transiently to the Cu ligands of SOD1, which are all contained within the folding nucleus. Then, after the global folding transition has commenced, the Zn2+ ion transfers to the higher affinity Zn site, which structures only very late in the folding process. Here it remains dynamically coordinated with an off rate of similar to 10(-5) s(-1). This relatively rapid equilibration of metals in and out of the SOD1 structure provides a simple explanation for how the exceptionally long lifetime, >100 years, of holoSOD1 is still compatible with cellular turnover: if a dissociated Zn2+ ion is prevented from rebinding to the SOD1 structure then the lifetime of the protein is reduced to a just a few hours.},
  author       = {Leinartaite, Lina and Kadhirvel, Saraboji and Nordlund, Anna and Logan, Derek and Oliveberg, Mikael},
  issn         = {1520-5126},
  language     = {eng},
  number       = {38},
  pages        = {13495--13504},
  publisher    = {The American Chemical Society},
  series       = {Journal of the American Chemical Society},
  title        = {Folding Catalysis by Transient Coordination of Zn2+ to the Cu Ligands of the ALS-Associated Enzyme Cu/Zn Superoxide Dismutase 1},
  url          = {http://dx.doi.org/10.1021/ja1057136},
  volume       = {132},
  year         = {2010},
}