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The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model
Aggregation of Cu–Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, amyotrophic lateral sclerosis (ALS). Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysi...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087447/ https://www.ncbi.nlm.nih.gov/pubmed/33825682 http://dx.doi.org/10.7554/eLife.61453 |
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author | Sannigrahi, Achinta Chowdhury, Sourav Das, Bidisha Banerjee, Amrita Halder, Animesh Kumar, Amaresh Saleem, Mohammed Naganathan, Athi N Karmakar, Sanat Chattopadhyay, Krishnananda |
author_facet | Sannigrahi, Achinta Chowdhury, Sourav Das, Bidisha Banerjee, Amrita Halder, Animesh Kumar, Amaresh Saleem, Mohammed Naganathan, Athi N Karmakar, Sanat Chattopadhyay, Krishnananda |
author_sort | Sannigrahi, Achinta |
collection | PubMed |
description | Aggregation of Cu–Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, amyotrophic lateral sclerosis (ALS). Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid-induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a ‘co-factor derived membrane association model’ wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association-mediated toxic aggregation and survival time scale after ALS diagnosis. |
format | Online Article Text |
id | pubmed-8087447 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-80874472021-05-03 The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model Sannigrahi, Achinta Chowdhury, Sourav Das, Bidisha Banerjee, Amrita Halder, Animesh Kumar, Amaresh Saleem, Mohammed Naganathan, Athi N Karmakar, Sanat Chattopadhyay, Krishnananda eLife Structural Biology and Molecular Biophysics Aggregation of Cu–Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, amyotrophic lateral sclerosis (ALS). Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid-induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a ‘co-factor derived membrane association model’ wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association-mediated toxic aggregation and survival time scale after ALS diagnosis. eLife Sciences Publications, Ltd 2021-04-07 /pmc/articles/PMC8087447/ /pubmed/33825682 http://dx.doi.org/10.7554/eLife.61453 Text en © 2021, Sannigrahi et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Structural Biology and Molecular Biophysics Sannigrahi, Achinta Chowdhury, Sourav Das, Bidisha Banerjee, Amrita Halder, Animesh Kumar, Amaresh Saleem, Mohammed Naganathan, Athi N Karmakar, Sanat Chattopadhyay, Krishnananda The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model |
title | The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model |
title_full | The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model |
title_fullStr | The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model |
title_full_unstemmed | The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model |
title_short | The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model |
title_sort | metal cofactor zinc and interacting membranes modulate sod1 conformation-aggregation landscape in an in vitro als model |
topic | Structural Biology and Molecular Biophysics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087447/ https://www.ncbi.nlm.nih.gov/pubmed/33825682 http://dx.doi.org/10.7554/eLife.61453 |
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