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Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer

Anomalous self-assembly of the Aβ peptide into fibrillar amyloid deposits is strongly correlated with the development of Alzheimer's disease. Aβ fibril extension follows a template guided “dock and lock” mechanism where polymerisation is catalysed by the fibrillar ends. Using surface plasmon re...

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Detalles Bibliográficos
Autores principales: Brännström, Kristoffer, Öhman, Anders, Olofsson, Anders
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182996/
https://www.ncbi.nlm.nih.gov/pubmed/21980388
http://dx.doi.org/10.1371/journal.pone.0025157
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author Brännström, Kristoffer
Öhman, Anders
Olofsson, Anders
author_facet Brännström, Kristoffer
Öhman, Anders
Olofsson, Anders
author_sort Brännström, Kristoffer
collection PubMed
description Anomalous self-assembly of the Aβ peptide into fibrillar amyloid deposits is strongly correlated with the development of Alzheimer's disease. Aβ fibril extension follows a template guided “dock and lock” mechanism where polymerisation is catalysed by the fibrillar ends. Using surface plasmon resonance (SPR) and quenched hydrogen-deuterium exchange NMR (H/D-exchange NMR), we have analysed the fibrillar structure and polymerisation properties of both the highly aggregation prone Aβ1–40 Glu22Gly (Aβ(40Arc)) and wild type Aβ1–40 (Aβ(40WT)). The solvent protection patterns from H/D exchange experiments suggest very similar structures of the fibrillar forms. However, through cross-seeding experiments monitored by SPR, we found that the monomeric form of Aβ(40WT) is significantly impaired to acquire the fibrillar architecture of Aβ(40Arc). A detailed characterisation demonstrated that Aβ(40WT) has a restricted ability to dock and isomerise with high binding affinity onto Aβ(40Arc) fibrils. These results have general implications for the process of fibril assembly, where the rate of polymerisation, and consequently the architecture of the formed fibrils, is restricted by conformational constraints of the monomers. Interestingly, we also found that the kinetic rate of fibril formation rather than the thermodynamically lowest energy state determines the overall fibrillar structure.
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spelling pubmed-31829962011-10-06 Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer Brännström, Kristoffer Öhman, Anders Olofsson, Anders PLoS One Research Article Anomalous self-assembly of the Aβ peptide into fibrillar amyloid deposits is strongly correlated with the development of Alzheimer's disease. Aβ fibril extension follows a template guided “dock and lock” mechanism where polymerisation is catalysed by the fibrillar ends. Using surface plasmon resonance (SPR) and quenched hydrogen-deuterium exchange NMR (H/D-exchange NMR), we have analysed the fibrillar structure and polymerisation properties of both the highly aggregation prone Aβ1–40 Glu22Gly (Aβ(40Arc)) and wild type Aβ1–40 (Aβ(40WT)). The solvent protection patterns from H/D exchange experiments suggest very similar structures of the fibrillar forms. However, through cross-seeding experiments monitored by SPR, we found that the monomeric form of Aβ(40WT) is significantly impaired to acquire the fibrillar architecture of Aβ(40Arc). A detailed characterisation demonstrated that Aβ(40WT) has a restricted ability to dock and isomerise with high binding affinity onto Aβ(40Arc) fibrils. These results have general implications for the process of fibril assembly, where the rate of polymerisation, and consequently the architecture of the formed fibrils, is restricted by conformational constraints of the monomers. Interestingly, we also found that the kinetic rate of fibril formation rather than the thermodynamically lowest energy state determines the overall fibrillar structure. Public Library of Science 2011-09-29 /pmc/articles/PMC3182996/ /pubmed/21980388 http://dx.doi.org/10.1371/journal.pone.0025157 Text en Brännström 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
Brännström, Kristoffer
Öhman, Anders
Olofsson, Anders
Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer
title Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer
title_full Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer
title_fullStr Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer
title_full_unstemmed Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer
title_short Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer
title_sort aβ peptide fibrillar architectures controlled by conformational constraints of the monomer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182996/
https://www.ncbi.nlm.nih.gov/pubmed/21980388
http://dx.doi.org/10.1371/journal.pone.0025157
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