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Amyloid β 42 fibril structure based on small-angle scattering
Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid β42 peptide (Aβ42) in Alzheimer’s disease. These fibrils are a source of toxicity to neuronal cells through surface-catalyzed generation of toxic oligomers. Detailed knowledge of the fibril struc...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640717/ https://www.ncbi.nlm.nih.gov/pubmed/34815346 http://dx.doi.org/10.1073/pnas.2112783118 |
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author | Lattanzi, Veronica André, Ingemar Gasser, Urs Dubackic, Marija Olsson, Ulf Linse, Sara |
author_facet | Lattanzi, Veronica André, Ingemar Gasser, Urs Dubackic, Marija Olsson, Ulf Linse, Sara |
author_sort | Lattanzi, Veronica |
collection | PubMed |
description | Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid β42 peptide (Aβ42) in Alzheimer’s disease. These fibrils are a source of toxicity to neuronal cells through surface-catalyzed generation of toxic oligomers. Detailed knowledge of the fibril structure may thus facilitate therapeutic development. We use small-angle scattering to provide information on the fibril cross-section dimension and shape for Aβ42 fibrils prepared in aqueous phosphate buffer at pH = 7.4 and pH 8.0 under quiescent conditions at 37 °C from pure recombinant Aβ42 peptide. Fitting the data using a continuum model reveals an elliptical cross-section and a peptide mass-per-unit length compatible with two filaments of two monomers, four monomers per plane. To provide a more detailed atomistic model, the data were fitted using as a starting state a high-resolution structure of the two-monomer arrangement in filaments from solid-state NMR (Protein Data Bank ID 5kk3). First, a twofold symmetric model including residues 11 to 42 of two monomers in the filament was optimized in terms of twist angle and local packing using Rosetta. A two-filament model was then built and optimized through fitting to the scattering data allowing the two N-termini in each filament to take different conformations, with the same conformation in each of the two filaments. This provides an atomistic model of the fibril with twofold rotation symmetry around the fibril axis. Intriguingly, no polydispersity as regards the number of filaments was observed in our system over separate samples, suggesting that the two-filament arrangement represents a free energy minimum for the Aβ42 fibril. |
format | Online Article Text |
id | pubmed-8640717 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-86407172021-12-13 Amyloid β 42 fibril structure based on small-angle scattering Lattanzi, Veronica André, Ingemar Gasser, Urs Dubackic, Marija Olsson, Ulf Linse, Sara Proc Natl Acad Sci U S A Physical Sciences Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid β42 peptide (Aβ42) in Alzheimer’s disease. These fibrils are a source of toxicity to neuronal cells through surface-catalyzed generation of toxic oligomers. Detailed knowledge of the fibril structure may thus facilitate therapeutic development. We use small-angle scattering to provide information on the fibril cross-section dimension and shape for Aβ42 fibrils prepared in aqueous phosphate buffer at pH = 7.4 and pH 8.0 under quiescent conditions at 37 °C from pure recombinant Aβ42 peptide. Fitting the data using a continuum model reveals an elliptical cross-section and a peptide mass-per-unit length compatible with two filaments of two monomers, four monomers per plane. To provide a more detailed atomistic model, the data were fitted using as a starting state a high-resolution structure of the two-monomer arrangement in filaments from solid-state NMR (Protein Data Bank ID 5kk3). First, a twofold symmetric model including residues 11 to 42 of two monomers in the filament was optimized in terms of twist angle and local packing using Rosetta. A two-filament model was then built and optimized through fitting to the scattering data allowing the two N-termini in each filament to take different conformations, with the same conformation in each of the two filaments. This provides an atomistic model of the fibril with twofold rotation symmetry around the fibril axis. Intriguingly, no polydispersity as regards the number of filaments was observed in our system over separate samples, suggesting that the two-filament arrangement represents a free energy minimum for the Aβ42 fibril. National Academy of Sciences 2021-11-23 2021-11-30 /pmc/articles/PMC8640717/ /pubmed/34815346 http://dx.doi.org/10.1073/pnas.2112783118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Physical Sciences Lattanzi, Veronica André, Ingemar Gasser, Urs Dubackic, Marija Olsson, Ulf Linse, Sara Amyloid β 42 fibril structure based on small-angle scattering |
title | Amyloid β 42 fibril structure based on small-angle scattering |
title_full | Amyloid β 42 fibril structure based on small-angle scattering |
title_fullStr | Amyloid β 42 fibril structure based on small-angle scattering |
title_full_unstemmed | Amyloid β 42 fibril structure based on small-angle scattering |
title_short | Amyloid β 42 fibril structure based on small-angle scattering |
title_sort | amyloid β 42 fibril structure based on small-angle scattering |
topic | Physical Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640717/ https://www.ncbi.nlm.nih.gov/pubmed/34815346 http://dx.doi.org/10.1073/pnas.2112783118 |
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