Stability of Transmembrane Amyloid ß-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aß$_{42}$ Mutations
Interactions of the amyloid β-protein (Aβ) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer’s disease. Natural mutations in Aβ42, such as the Arctic mutation (E22G) have been shown to increase Aβ42 aggreg...
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ftfzjuelichnvdb:oai:juser.fz-juelich.de:140002 2023-05-15T15:11:22+02:00 Stability of Transmembrane Amyloid ß-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aß$_{42}$ Mutations Poojari, Chetan Strodel, Birgit DE 2013 https://juser.fz-juelich.de/record/140002 https://juser.fz-juelich.de/search?p=id:%22FZJ-2013-05969%22 eng eng PLoS info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0078399 info:eu-repo/semantics/altIdentifier/issn/1932-6203 info:eu-repo/semantics/altIdentifier/wos/WOS:000327162900014 info:eu-repo/semantics/altIdentifier/hdl/2128/5651 https://juser.fz-juelich.de/record/140002 https://juser.fz-juelich.de/search?p=id:%22FZJ-2013-05969%22 info:eu-repo/semantics/openAccess PLoS one 8(11), e78399 (2013). doi:10.1371/journal.pone.0078399 info:eu-repo/classification/ddc/500 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2013 ftfzjuelichnvdb https://doi.org/10.1371/journal.pone.0078399 2022-07-14T11:03:01Z Interactions of the amyloid β-protein (Aβ) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer’s disease. Natural mutations in Aβ42, such as the Arctic mutation (E22G) have been shown to increase Aβ42 aggregation and neurotoxicity, leading to the early-onset of Alzheimer’s disease. A correlation between the propensity of Aβ42 to form protofibrils and its effect on neuronal dysfunction and degeneration has been established. Using rational mutagenesis of the Aβ42 peptide it was further revealed that the aggregation of different Aβ42 mutants in lipid membranes results in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also have a variable ability to disrupt bilayer integrity. To further test the connection between Aβ42 mutation and peptide–membrane interactions, we perform molecular dynamics simulations of membrane-inserted Aβ42 variants (wild-type and E22G, D23G, E22G/D23G, K16M/K28M and K16M/E22G/D23G/K28M mutants) as β-sheet monomers and tetramers. The effects of charged residues on transmembrane Aβ42 stability and membrane integrity are analyzed at atomistic level. We observe an increased stability for the E22G Aβ42 peptide and a decreased stability for D23G compared to wild-type Aβ42, while D23G has the largest membrane-disruptive effect. These results support the experimental observation that the altered toxicity arising from mutations in Aβ is not only a result of the altered aggregation propensity, but also originates from modified Aβ interactions with neuronal membranes. Article in Journal/Newspaper Arctic Forschungszentrum Jülich: JuSER (Juelich Shared Electronic Resources) Arctic PLoS ONE 8 11 e78399 |
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Forschungszentrum Jülich: JuSER (Juelich Shared Electronic Resources) |
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English |
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info:eu-repo/classification/ddc/500 Poojari, Chetan Strodel, Birgit Stability of Transmembrane Amyloid ß-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aß$_{42}$ Mutations |
topic_facet |
info:eu-repo/classification/ddc/500 |
description |
Interactions of the amyloid β-protein (Aβ) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer’s disease. Natural mutations in Aβ42, such as the Arctic mutation (E22G) have been shown to increase Aβ42 aggregation and neurotoxicity, leading to the early-onset of Alzheimer’s disease. A correlation between the propensity of Aβ42 to form protofibrils and its effect on neuronal dysfunction and degeneration has been established. Using rational mutagenesis of the Aβ42 peptide it was further revealed that the aggregation of different Aβ42 mutants in lipid membranes results in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also have a variable ability to disrupt bilayer integrity. To further test the connection between Aβ42 mutation and peptide–membrane interactions, we perform molecular dynamics simulations of membrane-inserted Aβ42 variants (wild-type and E22G, D23G, E22G/D23G, K16M/K28M and K16M/E22G/D23G/K28M mutants) as β-sheet monomers and tetramers. The effects of charged residues on transmembrane Aβ42 stability and membrane integrity are analyzed at atomistic level. We observe an increased stability for the E22G Aβ42 peptide and a decreased stability for D23G compared to wild-type Aβ42, while D23G has the largest membrane-disruptive effect. These results support the experimental observation that the altered toxicity arising from mutations in Aβ is not only a result of the altered aggregation propensity, but also originates from modified Aβ interactions with neuronal membranes. |
format |
Article in Journal/Newspaper |
author |
Poojari, Chetan Strodel, Birgit |
author_facet |
Poojari, Chetan Strodel, Birgit |
author_sort |
Poojari, Chetan |
title |
Stability of Transmembrane Amyloid ß-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aß$_{42}$ Mutations |
title_short |
Stability of Transmembrane Amyloid ß-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aß$_{42}$ Mutations |
title_full |
Stability of Transmembrane Amyloid ß-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aß$_{42}$ Mutations |
title_fullStr |
Stability of Transmembrane Amyloid ß-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aß$_{42}$ Mutations |
title_full_unstemmed |
Stability of Transmembrane Amyloid ß-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aß$_{42}$ Mutations |
title_sort |
stability of transmembrane amyloid ß-peptide and membrane integrity tested by molecular modeling of site-specific aß$_{42}$ mutations |
publisher |
PLoS |
publishDate |
2013 |
url |
https://juser.fz-juelich.de/record/140002 https://juser.fz-juelich.de/search?p=id:%22FZJ-2013-05969%22 |
op_coverage |
DE |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS one 8(11), e78399 (2013). doi:10.1371/journal.pone.0078399 |
op_relation |
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0078399 info:eu-repo/semantics/altIdentifier/issn/1932-6203 info:eu-repo/semantics/altIdentifier/wos/WOS:000327162900014 info:eu-repo/semantics/altIdentifier/hdl/2128/5651 https://juser.fz-juelich.de/record/140002 https://juser.fz-juelich.de/search?p=id:%22FZJ-2013-05969%22 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.1371/journal.pone.0078399 |
container_title |
PLoS ONE |
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8 |
container_issue |
11 |
container_start_page |
e78399 |
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1766342226174017536 |