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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...

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Autores principales: Sannigrahi, Achinta, Chowdhury, Sourav, Das, Bidisha, Banerjee, Amrita, Halder, Animesh, Kumar, Amaresh, Saleem, Mohammed, Naganathan, Athi N, Karmakar, Sanat, Chattopadhyay, Krishnananda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
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.
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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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