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Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy

Oligomeric aggregates are widely suspected as toxic agents in diseases caused by protein aggregation, yet they remain poorly characterized, partly because they are challenging to isolate from a heterogeneous mixture of species. We developed an assay for characterizing structure, stability, and kinet...

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Detalles Bibliográficos
Autores principales: Neupane, Krishna, Solanki, Allison, Sosova, Iveta, Belov, Miro, Woodside, Michael T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901707/
https://www.ncbi.nlm.nih.gov/pubmed/24475132
http://dx.doi.org/10.1371/journal.pone.0086495
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author Neupane, Krishna
Solanki, Allison
Sosova, Iveta
Belov, Miro
Woodside, Michael T.
author_facet Neupane, Krishna
Solanki, Allison
Sosova, Iveta
Belov, Miro
Woodside, Michael T.
author_sort Neupane, Krishna
collection PubMed
description Oligomeric aggregates are widely suspected as toxic agents in diseases caused by protein aggregation, yet they remain poorly characterized, partly because they are challenging to isolate from a heterogeneous mixture of species. We developed an assay for characterizing structure, stability, and kinetics of individual oligomers at high resolution and sensitivity using single-molecule force spectroscopy, and applied it to observe the formation of transient structured aggregates within single oligomers of α-synuclein, an intrinsically-disordered protein linked to Parkinson’s disease. Measurements of the molecular extension as the proteins unfolded under tension in optical tweezers revealed that even small oligomers could form numerous metastable structures, with a surprisingly broad range of sizes. Comparing the structures formed in monomers, dimers and tetramers, we found that the average mechanical stability increased with oligomer size. Most structures formed within a minute, with size-dependent rates. These results provide a new window onto the complex α-synuclein aggregation landscape, characterizing the microscopic structural heterogeneity and kinetics of different pathways.
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spelling pubmed-39017072014-01-28 Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy Neupane, Krishna Solanki, Allison Sosova, Iveta Belov, Miro Woodside, Michael T. PLoS One Research Article Oligomeric aggregates are widely suspected as toxic agents in diseases caused by protein aggregation, yet they remain poorly characterized, partly because they are challenging to isolate from a heterogeneous mixture of species. We developed an assay for characterizing structure, stability, and kinetics of individual oligomers at high resolution and sensitivity using single-molecule force spectroscopy, and applied it to observe the formation of transient structured aggregates within single oligomers of α-synuclein, an intrinsically-disordered protein linked to Parkinson’s disease. Measurements of the molecular extension as the proteins unfolded under tension in optical tweezers revealed that even small oligomers could form numerous metastable structures, with a surprisingly broad range of sizes. Comparing the structures formed in monomers, dimers and tetramers, we found that the average mechanical stability increased with oligomer size. Most structures formed within a minute, with size-dependent rates. These results provide a new window onto the complex α-synuclein aggregation landscape, characterizing the microscopic structural heterogeneity and kinetics of different pathways. Public Library of Science 2014-01-24 /pmc/articles/PMC3901707/ /pubmed/24475132 http://dx.doi.org/10.1371/journal.pone.0086495 Text en © 2014 Neupane et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Neupane, Krishna
Solanki, Allison
Sosova, Iveta
Belov, Miro
Woodside, Michael T.
Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy
title Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy
title_full Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy
title_fullStr Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy
title_full_unstemmed Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy
title_short Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy
title_sort diverse metastable structures formed by small oligomers of α-synuclein probed by force spectroscopy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901707/
https://www.ncbi.nlm.nih.gov/pubmed/24475132
http://dx.doi.org/10.1371/journal.pone.0086495
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