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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/07296 |
| _version_ | 1811253360359112704 |
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| author | Ashok Sekhar Jessica AO Rumfeldt Helen R Broom Colleen M Doyle Guillaume Bouvignies Elizabeth M Meiering Lewis E Kay |
| author_facet | Ashok Sekhar Jessica AO Rumfeldt Helen R Broom Colleen M Doyle Guillaume Bouvignies Elizabeth M Meiering Lewis E Kay |
| author_sort | Ashok Sekhar |
| collection | DOAJ |
| 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 (apoSOD12SH). 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 apoSOD12SH 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. |
| first_indexed | 2024-04-12T16:49:43Z |
| format | Article |
| id | doaj.art-3e6f47c6b96f48569f57e0bce025c0fc |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:49:43Z |
| publishDate | 2015-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3e6f47c6b96f48569f57e0bce025c0fc2022-12-22T03:24:26ZengeLife Sciences Publications LtdeLife2050-084X2015-06-01410.7554/eLife.07296Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathwaysAshok Sekhar0Jessica AO Rumfeldt1Helen R Broom2Colleen M Doyle3Guillaume Bouvignies4Elizabeth M Meiering5Lewis E Kay6Department of Molecular Genetics, University of Toronto, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada; Department of Chemistry, University of Toronto, Toronto, CanadaDepartment of Chemistry, University of Waterloo, Waterloo, CanadaDepartment of Chemistry, University of Waterloo, Waterloo, CanadaDepartment of Chemistry, University of Waterloo, Waterloo, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada; Université Grenoble Alpes, Grenoble, France; Institut de Biologie Structurale, Centre National de la Recherche Scientifique, Grenoble, France; Institut de Biologie Structurale, Commissariat à l'énergie atomique, Grenoble, France; Department of Chemistry, University of Toronto, Toronto, CanadaDepartment of Chemistry, University of Waterloo, Waterloo, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada; Department of Chemistry, University of Toronto, Toronto, Canada; Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, CanadaAmyotrophic 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 (apoSOD12SH). 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 apoSOD12SH 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.https://elifesciences.org/articles/07296human Cu, Zn superoxide dismutaseCPMG relaxation dispersionnon-native oligomertransient conformationCESTprotein aggregation |
| spellingShingle | Ashok Sekhar Jessica AO Rumfeldt Helen R Broom Colleen M Doyle Guillaume Bouvignies Elizabeth M Meiering Lewis E Kay Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways eLife human Cu, Zn superoxide dismutase CPMG relaxation dispersion non-native oligomer transient conformation CEST protein aggregation |
| 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 | human Cu, Zn superoxide dismutase CPMG relaxation dispersion non-native oligomer transient conformation CEST protein aggregation |
| url | https://elifesciences.org/articles/07296 |
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