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A Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity

The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization... Full description

Journal Title: Journal of the American Chemical Society April 27, 2016, Vol.138(19), pp.6271-6280
Main Author: Karamanos, Theodoros
Other Authors: Pashley, Clare , Kalverda, Arnout , Thompson, Gary , Mayzel, Maxim , Orekhov, Vladislav , Radford, Sheena
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0002-7863 ; E-ISSN: 1520-5126 ; DOI: 10.1021/jacs.6b02464
Link: http://search.proquest.com/docview/1825553927/?pq-origsite=primo
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title: A Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity
format: Article
creator:
  • Karamanos, Theodoros
  • Pashley, Clare
  • Kalverda, Arnout
  • Thompson, Gary
  • Mayzel, Maxim
  • Orekhov, Vladislav
  • Radford, Sheena
subjects:
  • Determinants
  • Structural Analysis
  • Folding
  • Proteins
  • Assembly
  • Dynamics
  • Ablation
  • Agglomeration
  • Analysis (MD)
  • Chemical Analysis (Ep)
  • Chemical Analysis (Ed)
  • Chemical Analysis (EC)
ispartof: Journal of the American Chemical Society, April 27, 2016, Vol.138(19), pp.6271-6280
description: The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of beta 2-microglobulin ( beta 2m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone ITrans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
language: eng
source:
identifier: ISSN: 0002-7863 ; E-ISSN: 1520-5126 ; DOI: 10.1021/jacs.6b02464
fulltext: no_fulltext
issn:
  • 00027863
  • 0002-7863
  • 15205126
  • 1520-5126
url: Link


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titleA Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity
creatorKaramanos, Theodoros ; Pashley, Clare ; Kalverda, Arnout ; Thompson, Gary ; Mayzel, Maxim ; Orekhov, Vladislav ; Radford, Sheena
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subjectDeterminants ; Structural Analysis ; Folding ; Proteins ; Assembly ; Dynamics ; Ablation ; Agglomeration ; Analysis (MD) ; Chemical Analysis (Ep) ; Chemical Analysis (Ed) ; Chemical Analysis (EC)
descriptionThe balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of beta 2-microglobulin ( beta 2m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone ITrans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
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titleA Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity
descriptionThe balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of beta 2-microglobulin ( beta 2m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone ITrans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
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abstractThe balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of beta 2-microglobulin ( beta 2m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone ITrans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
doi10.1021/jacs.6b02464
urlhttp://search.proquest.com/docview/1825553927/
date2016-05-18