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Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1
Superoxide dismutase (SOD) is the primary enzyme of the cellular antioxidant defense cascade. Misfolding, concomitant oligomerization, and higher order aggregation of human cytosolic SOD are linked to amyotrophic lateral sclerosis (ALS). Although, with two metal ion cofactors SOD1 is extremely robus...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995586/ https://www.ncbi.nlm.nih.gov/pubmed/31817166 http://dx.doi.org/10.3390/biom9120826 |
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author | Chowdhury, Sourav Sanyal, Dwipanjan Sen, Sagnik Uversky, Vladimir N. Maulik, Ujjwal Chattopadhyay, Krishnananda |
author_facet | Chowdhury, Sourav Sanyal, Dwipanjan Sen, Sagnik Uversky, Vladimir N. Maulik, Ujjwal Chattopadhyay, Krishnananda |
author_sort | Chowdhury, Sourav |
collection | PubMed |
description | Superoxide dismutase (SOD) is the primary enzyme of the cellular antioxidant defense cascade. Misfolding, concomitant oligomerization, and higher order aggregation of human cytosolic SOD are linked to amyotrophic lateral sclerosis (ALS). Although, with two metal ion cofactors SOD1 is extremely robust, the de-metallated apo form is intrinsically disordered. Since the rise of oxygen-based metabolism and antioxidant defense systems are evolutionary coupled, SOD is an interesting protein with a deep evolutionary history. We deployed statistical analysis of sequence space to decode evolutionarily co-varying residues in this protein. These were validated by applying graph theoretical modelling to understand the impact of the presence of metal ion co-factors in dictating the disordered (apo) to hidden disordered (wild-type SOD1) transition. Contact maps were generated for different variants, and the selected significant residues were mapped on separate structure networks. Sequence space analysis coupled with structure networks helped us to map the evolutionarily coupled co-varying patches in the SOD1 and its metal-depleted variants. In addition, using structure network analysis, the residues with a major impact on the internal dynamics of the protein structure were investigated. Our results reveal that the bulk of these evolutionarily co-varying residues are localized in the loop regions and positioned differentially depending upon the metal residence and concomitant steric restrictions of the loops. |
format | Online Article Text |
id | pubmed-6995586 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69955862020-02-13 Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1 Chowdhury, Sourav Sanyal, Dwipanjan Sen, Sagnik Uversky, Vladimir N. Maulik, Ujjwal Chattopadhyay, Krishnananda Biomolecules Article Superoxide dismutase (SOD) is the primary enzyme of the cellular antioxidant defense cascade. Misfolding, concomitant oligomerization, and higher order aggregation of human cytosolic SOD are linked to amyotrophic lateral sclerosis (ALS). Although, with two metal ion cofactors SOD1 is extremely robust, the de-metallated apo form is intrinsically disordered. Since the rise of oxygen-based metabolism and antioxidant defense systems are evolutionary coupled, SOD is an interesting protein with a deep evolutionary history. We deployed statistical analysis of sequence space to decode evolutionarily co-varying residues in this protein. These were validated by applying graph theoretical modelling to understand the impact of the presence of metal ion co-factors in dictating the disordered (apo) to hidden disordered (wild-type SOD1) transition. Contact maps were generated for different variants, and the selected significant residues were mapped on separate structure networks. Sequence space analysis coupled with structure networks helped us to map the evolutionarily coupled co-varying patches in the SOD1 and its metal-depleted variants. In addition, using structure network analysis, the residues with a major impact on the internal dynamics of the protein structure were investigated. Our results reveal that the bulk of these evolutionarily co-varying residues are localized in the loop regions and positioned differentially depending upon the metal residence and concomitant steric restrictions of the loops. MDPI 2019-12-04 /pmc/articles/PMC6995586/ /pubmed/31817166 http://dx.doi.org/10.3390/biom9120826 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Chowdhury, Sourav Sanyal, Dwipanjan Sen, Sagnik Uversky, Vladimir N. Maulik, Ujjwal Chattopadhyay, Krishnananda Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1 |
title | Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1 |
title_full | Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1 |
title_fullStr | Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1 |
title_full_unstemmed | Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1 |
title_short | Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1 |
title_sort | evolutionary analyses of sequence and structure space unravel the structural facets of sod1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995586/ https://www.ncbi.nlm.nih.gov/pubmed/31817166 http://dx.doi.org/10.3390/biom9120826 |
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