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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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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. |
format | Online Article Text |
id | pubmed-3182996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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