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Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving cytotoxic conformations of Cu, Zn superoxide dismutase (SOD1). A major challenge in understanding ALS disease pathology has been the identification and atomic-level characterization of these conformers. Here, we...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475725/ https://www.ncbi.nlm.nih.gov/pubmed/26099300 http://dx.doi.org/10.7554/eLife.07296 |
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author | Sekhar, Ashok Rumfeldt, Jessica AO Broom, Helen R Doyle, Colleen M Bouvignies, Guillaume Meiering, Elizabeth M Kay, Lewis E |
author_facet | Sekhar, Ashok Rumfeldt, Jessica AO Broom, Helen R Doyle, Colleen M Bouvignies, Guillaume Meiering, Elizabeth M Kay, Lewis E |
author_sort | Sekhar, Ashok |
collection | PubMed |
description | Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving cytotoxic conformations of Cu, Zn superoxide dismutase (SOD1). A major challenge in understanding ALS disease pathology has been the identification and atomic-level characterization of these conformers. Here, we use a combination of NMR methods to detect four distinct sparsely populated and transiently formed thermally accessible conformers in equilibrium with the native state of immature SOD1 (apoSOD1(2SH)). Structural models of two of these establish that they possess features present in the mature dimeric protein. In contrast, the other two are non-native oligomers in which the native dimer interface and the electrostatic loop mediate the formation of aberrant intermolecular interactions. Our results show that apoSOD1(2SH) has a rugged free energy landscape that codes for distinct kinetic pathways leading to either maturation or non-native association and provide a starting point for a detailed atomic-level understanding of the mechanisms of SOD1 oligomerization. DOI: http://dx.doi.org/10.7554/eLife.07296.001 |
format | Online Article Text |
id | pubmed-4475725 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-44757252015-06-24 Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways Sekhar, Ashok Rumfeldt, Jessica AO Broom, Helen R Doyle, Colleen M Bouvignies, Guillaume Meiering, Elizabeth M Kay, Lewis E eLife Biophysics and Structural Biology Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving cytotoxic conformations of Cu, Zn superoxide dismutase (SOD1). A major challenge in understanding ALS disease pathology has been the identification and atomic-level characterization of these conformers. Here, we use a combination of NMR methods to detect four distinct sparsely populated and transiently formed thermally accessible conformers in equilibrium with the native state of immature SOD1 (apoSOD1(2SH)). Structural models of two of these establish that they possess features present in the mature dimeric protein. In contrast, the other two are non-native oligomers in which the native dimer interface and the electrostatic loop mediate the formation of aberrant intermolecular interactions. Our results show that apoSOD1(2SH) has a rugged free energy landscape that codes for distinct kinetic pathways leading to either maturation or non-native association and provide a starting point for a detailed atomic-level understanding of the mechanisms of SOD1 oligomerization. DOI: http://dx.doi.org/10.7554/eLife.07296.001 eLife Sciences Publications, Ltd 2015-06-23 /pmc/articles/PMC4475725/ /pubmed/26099300 http://dx.doi.org/10.7554/eLife.07296 Text en © 2015, Sekhar et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biophysics and Structural Biology Sekhar, Ashok Rumfeldt, Jessica AO Broom, Helen R Doyle, Colleen M Bouvignies, Guillaume Meiering, Elizabeth M Kay, Lewis E Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways |
title | Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways |
title_full | Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways |
title_fullStr | Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways |
title_full_unstemmed | Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways |
title_short | Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways |
title_sort | thermal fluctuations of immature sod1 lead to separate folding and misfolding pathways |
topic | Biophysics and Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475725/ https://www.ncbi.nlm.nih.gov/pubmed/26099300 http://dx.doi.org/10.7554/eLife.07296 |
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