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Plasticity of Membrane Binding by the Central Region of α-Synuclein

Membrane binding by α-synuclein (αS), an intrinsically disordered protein whose aggregation is associated with Parkinson’s disease, is a key step in determining its biological properties under both physiological and pathological conditions. Upon membrane interaction, αS retains a partial level of st...

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Autores principales: Navarro-Paya, Carlos, Sanz-Hernandez, Maximo, De Simone, Alfonso
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240306/
https://www.ncbi.nlm.nih.gov/pubmed/35782868
http://dx.doi.org/10.3389/fmolb.2022.857217
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author Navarro-Paya, Carlos
Sanz-Hernandez, Maximo
De Simone, Alfonso
author_facet Navarro-Paya, Carlos
Sanz-Hernandez, Maximo
De Simone, Alfonso
author_sort Navarro-Paya, Carlos
collection PubMed
description Membrane binding by α-synuclein (αS), an intrinsically disordered protein whose aggregation is associated with Parkinson’s disease, is a key step in determining its biological properties under both physiological and pathological conditions. Upon membrane interaction, αS retains a partial level of structural disorder despite acquiring α-helical content. In the membrane-bound state, the equilibrium between the helical-bound and disordered-detached states of the central region of αS (residues 65–97) has been involved in a double-anchor mechanism that promotes the clustering of synaptic vesicles. Herein, we investigated the underlying molecular bases of this equilibrium using enhanced coarse-grained molecular dynamics simulations. The results enabled clarifying the conformational dependencies of the membrane affinity by this protein region that, in addition to playing a role in physiological membrane binding, has key relevance for the aggregation of αS and the mechanisms of the toxicity of the resulting assemblies.
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spelling pubmed-92403062022-06-30 Plasticity of Membrane Binding by the Central Region of α-Synuclein Navarro-Paya, Carlos Sanz-Hernandez, Maximo De Simone, Alfonso Front Mol Biosci Molecular Biosciences Membrane binding by α-synuclein (αS), an intrinsically disordered protein whose aggregation is associated with Parkinson’s disease, is a key step in determining its biological properties under both physiological and pathological conditions. Upon membrane interaction, αS retains a partial level of structural disorder despite acquiring α-helical content. In the membrane-bound state, the equilibrium between the helical-bound and disordered-detached states of the central region of αS (residues 65–97) has been involved in a double-anchor mechanism that promotes the clustering of synaptic vesicles. Herein, we investigated the underlying molecular bases of this equilibrium using enhanced coarse-grained molecular dynamics simulations. The results enabled clarifying the conformational dependencies of the membrane affinity by this protein region that, in addition to playing a role in physiological membrane binding, has key relevance for the aggregation of αS and the mechanisms of the toxicity of the resulting assemblies. Frontiers Media S.A. 2022-06-15 /pmc/articles/PMC9240306/ /pubmed/35782868 http://dx.doi.org/10.3389/fmolb.2022.857217 Text en Copyright © 2022 Navarro-Paya, Sanz-Hernandez and De Simone. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Navarro-Paya, Carlos
Sanz-Hernandez, Maximo
De Simone, Alfonso
Plasticity of Membrane Binding by the Central Region of α-Synuclein
title Plasticity of Membrane Binding by the Central Region of α-Synuclein
title_full Plasticity of Membrane Binding by the Central Region of α-Synuclein
title_fullStr Plasticity of Membrane Binding by the Central Region of α-Synuclein
title_full_unstemmed Plasticity of Membrane Binding by the Central Region of α-Synuclein
title_short Plasticity of Membrane Binding by the Central Region of α-Synuclein
title_sort plasticity of membrane binding by the central region of α-synuclein
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240306/
https://www.ncbi.nlm.nih.gov/pubmed/35782868
http://dx.doi.org/10.3389/fmolb.2022.857217
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