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Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States

Parkinson’s disease is the second most common neurodegenerative disorder, in which both alpha-synuclein (α-syn) and dopamine (DA) have a critical role. α-Syn is known to be natively unstructured in equilibrium with subpopulations of more compact structures. It is these compact structures that are th...

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Autores principales: Illes-Toth, Eva, Dalton, Caroline F., Smith, David P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738842/
https://www.ncbi.nlm.nih.gov/pubmed/23817832
http://dx.doi.org/10.1007/s13361-013-0676-z
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author Illes-Toth, Eva
Dalton, Caroline F.
Smith, David P.
author_facet Illes-Toth, Eva
Dalton, Caroline F.
Smith, David P.
author_sort Illes-Toth, Eva
collection PubMed
description Parkinson’s disease is the second most common neurodegenerative disorder, in which both alpha-synuclein (α-syn) and dopamine (DA) have a critical role. α-Syn is known to be natively unstructured in equilibrium with subpopulations of more compact structures. It is these compact structures that are thought to be linked to amyloid formation. In the presence of DA, α-syn yields a diverse range of SDS-resistant, non-amyloid oligomers, however the precursor state conformation has not been established. Here, three DA molecules have been observed to bind per α-syn monomer by electrospray-ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS). Each of these DA molecules binds exclusively to the extended conformation of α-syn, and binding is not observed in the compact state of the protein. Measurements of collisional cross sectional areas show that the incremental uptake of DA pushes the protein towards a highly extended population, becoming fully populated upon the binding of three DA ligands. Tyrosine (Tyr) as a closely related structural analog, exhibited limited binding to the protein as compared with DA, with a maximum of two ligands being observed. Those Tyr ligands that do bind were observed as adducts to the extended conformation akin to DA. These findings suggest DA is able to modulate α-syn self-assembly by inducing the population of a highly extended state. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13361-013-0676-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-37388422013-08-13 Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States Illes-Toth, Eva Dalton, Caroline F. Smith, David P. J Am Soc Mass Spectrom Research Article Parkinson’s disease is the second most common neurodegenerative disorder, in which both alpha-synuclein (α-syn) and dopamine (DA) have a critical role. α-Syn is known to be natively unstructured in equilibrium with subpopulations of more compact structures. It is these compact structures that are thought to be linked to amyloid formation. In the presence of DA, α-syn yields a diverse range of SDS-resistant, non-amyloid oligomers, however the precursor state conformation has not been established. Here, three DA molecules have been observed to bind per α-syn monomer by electrospray-ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS). Each of these DA molecules binds exclusively to the extended conformation of α-syn, and binding is not observed in the compact state of the protein. Measurements of collisional cross sectional areas show that the incremental uptake of DA pushes the protein towards a highly extended population, becoming fully populated upon the binding of three DA ligands. Tyrosine (Tyr) as a closely related structural analog, exhibited limited binding to the protein as compared with DA, with a maximum of two ligands being observed. Those Tyr ligands that do bind were observed as adducts to the extended conformation akin to DA. These findings suggest DA is able to modulate α-syn self-assembly by inducing the population of a highly extended state. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13361-013-0676-z) contains supplementary material, which is available to authorized users. Springer US 2013-07-02 2013 /pmc/articles/PMC3738842/ /pubmed/23817832 http://dx.doi.org/10.1007/s13361-013-0676-z Text en © The Author(s) 2013 https://creativecommons.org/licenses/by/2.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Research Article
Illes-Toth, Eva
Dalton, Caroline F.
Smith, David P.
Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States
title Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States
title_full Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States
title_fullStr Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States
title_full_unstemmed Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States
title_short Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States
title_sort binding of dopamine to alpha-synuclein is mediated by specific conformational states
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738842/
https://www.ncbi.nlm.nih.gov/pubmed/23817832
http://dx.doi.org/10.1007/s13361-013-0676-z
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