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Functional features cause misfolding of the ALS-provoking enzyme SOD1

Nordlund, Anna; Leinartaite, Lina; Kadhirvel, Saraboji LU ; Aisenbrey, Christopher; Grobner, Gerhard; Zetterstrom, Per; Danielsson, Jens; Logan, Derek LU and Oliveberg, Mikael (2009) In Proceedings of the National Academy of Sciences 106(24). p.9667-9672
Abstract
The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically on the correct coordination of Cu and Zn. Loss of these cofactors not only promotes SOD1 aggregation in vitro but also seems to be a key prerequisite for pathogenic misfolding in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We examine here the consequences of Zn2+ loss by selectively removing the Zn site, which has been implicated as the main modulator of SOD1 stability and disease competence. After Zn-site removal, the remaining Cu ligands can coordinate a non-native Zn2+ ion with mu M affinity in the denatured state, and then retain this ion throughout the folding reaction. Without the restriction of a metallated Zn site,... (More)
The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically on the correct coordination of Cu and Zn. Loss of these cofactors not only promotes SOD1 aggregation in vitro but also seems to be a key prerequisite for pathogenic misfolding in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We examine here the consequences of Zn2+ loss by selectively removing the Zn site, which has been implicated as the main modulator of SOD1 stability and disease competence. After Zn-site removal, the remaining Cu ligands can coordinate a non-native Zn2+ ion with mu M affinity in the denatured state, and then retain this ion throughout the folding reaction. Without the restriction of a metallated Zn site, however, the Cu ligands fail to correctly coordinate the nonnative Zn2+ ion: Trapping of a water molecule causes H48 to change rotamer and swing outwards. The misligation is sterically incompatible with the native structure. As a consequence, SOD1 unfolds locally and interacts with neighboring molecules in the crystal lattice. The findings point to a critical role for the native Zn site in controlling SOD1 misfolding, and show that even subtle changes of the metal-loading sequence can render the wild-type protein the same structural properties as ALS-provoking mutations. This frustrated character of the SOD1 molecule seems to arise from a compromise between optimization of functional and structural features. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
functional evolution, protein misfolding, protein disease
in
Proceedings of the National Academy of Sciences
volume
106
issue
24
pages
9667 - 9672
publisher
National Acad Sciences
external identifiers
  • wos:000267045500024
  • scopus:67649852607
ISSN
1091-6490
DOI
10.1073/pnas.0812046106
language
English
LU publication?
yes
id
a17d1446-157f-4afd-a356-7d7eeb1c2708 (old id 1441575)
date added to LUP
2009-07-28 08:27:36
date last changed
2017-10-22 03:42:04
@article{a17d1446-157f-4afd-a356-7d7eeb1c2708,
  abstract     = {The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically on the correct coordination of Cu and Zn. Loss of these cofactors not only promotes SOD1 aggregation in vitro but also seems to be a key prerequisite for pathogenic misfolding in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We examine here the consequences of Zn2+ loss by selectively removing the Zn site, which has been implicated as the main modulator of SOD1 stability and disease competence. After Zn-site removal, the remaining Cu ligands can coordinate a non-native Zn2+ ion with mu M affinity in the denatured state, and then retain this ion throughout the folding reaction. Without the restriction of a metallated Zn site, however, the Cu ligands fail to correctly coordinate the nonnative Zn2+ ion: Trapping of a water molecule causes H48 to change rotamer and swing outwards. The misligation is sterically incompatible with the native structure. As a consequence, SOD1 unfolds locally and interacts with neighboring molecules in the crystal lattice. The findings point to a critical role for the native Zn site in controlling SOD1 misfolding, and show that even subtle changes of the metal-loading sequence can render the wild-type protein the same structural properties as ALS-provoking mutations. This frustrated character of the SOD1 molecule seems to arise from a compromise between optimization of functional and structural features.},
  author       = {Nordlund, Anna and Leinartaite, Lina and Kadhirvel, Saraboji and Aisenbrey, Christopher and Grobner, Gerhard and Zetterstrom, Per and Danielsson, Jens and Logan, Derek and Oliveberg, Mikael},
  issn         = {1091-6490},
  keyword      = {functional evolution,protein misfolding,protein disease},
  language     = {eng},
  number       = {24},
  pages        = {9667--9672},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Functional features cause misfolding of the ALS-provoking enzyme SOD1},
  url          = {http://dx.doi.org/10.1073/pnas.0812046106},
  volume       = {106},
  year         = {2009},
}