On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations
The aggregation of the amyloid-β (Aβ) peptide is linked to the pathogenesis of Alzheimer’s disease (AD). In particular, some point mutations within Aβ are associated with early-onset familial Alzheimer’s disease. Here we set out to explore how the physical properties of the altered side chains, incl...
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ftulundlup:oai:lup.lub.lu.se:cb6a140e-e66d-4113-82fc-59fbd5b5956f 2024-05-19T07:36:30+00:00 On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations Yang, Xiaoting Meisl, Georg Frohm, Birgitta Thulin, Eva Knowles, Tuomas P.J. Linse, Sara 2018-06-26 https://lup.lub.lu.se/record/cb6a140e-e66d-4113-82fc-59fbd5b5956f https://doi.org/10.1073/pnas.1803539115 eng eng National Academy of Sciences https://lup.lub.lu.se/record/cb6a140e-e66d-4113-82fc-59fbd5b5956f http://dx.doi.org/10.1073/pnas.1803539115 scopus:85049050338 pmid:29895690 Proceedings of the National Academy of Sciences of the United States of America; 115(26), pp 5849-5858 (2018) ISSN: 0027-8424 Medicinal Chemistry Cell and Molecular Biology Aggregation mechanism Amyloid Driving forces Kinetic analysis Self-assembly contributiontojournal/article info:eu-repo/semantics/article text 2018 ftulundlup https://doi.org/10.1073/pnas.1803539115 2024-04-30T23:40:11Z The aggregation of the amyloid-β (Aβ) peptide is linked to the pathogenesis of Alzheimer’s disease (AD). In particular, some point mutations within Aβ are associated with early-onset familial Alzheimer’s disease. Here we set out to explore how the physical properties of the altered side chains, including their sizes and charges, affect the molecular mechanisms of aggregation. We focus on Aβ42 with familial mutations—A21G (Flemish), E22K (Italian), E22G (Arctic), E22Q (Dutch), and D23N (Iowa)—which lead to similar or identical pathology with sporadic AD or severe cerebral amyloid angiopathy. Through global kinetic analysis, we find that for the E22K, E22G, E22Q, and D23N mutations, the acceleration of the overall aggregation originates primarily from the modulation of the nucleation processes, in particular secondary nucleation on the surface of existing fibrils, whereas the elongation process is not significantly affected. Remarkably, the D23 position appears to be responsible for most of the charge effects during nucleation, while the size of the side chain at the E22 position plays a more significant role than its charge. Thus, we have developed a kinetic approach to determine the nature and the magnitude of the contribution of specific residues to the rate of individual steps of the aggregation reaction, through targeted mutations and variations in ionic strength. This strategy can help rationalize the effect of some disease-related mutations as well as yield insights into the mechanism of aggregation and the transition states of the wild-type protein. Article in Journal/Newspaper Arctic Lund University Publications (LUP) Proceedings of the National Academy of Sciences 115 26 E5849 E5858 |
institution |
Open Polar |
collection |
Lund University Publications (LUP) |
op_collection_id |
ftulundlup |
language |
English |
topic |
Medicinal Chemistry Cell and Molecular Biology Aggregation mechanism Amyloid Driving forces Kinetic analysis Self-assembly |
spellingShingle |
Medicinal Chemistry Cell and Molecular Biology Aggregation mechanism Amyloid Driving forces Kinetic analysis Self-assembly Yang, Xiaoting Meisl, Georg Frohm, Birgitta Thulin, Eva Knowles, Tuomas P.J. Linse, Sara On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations |
topic_facet |
Medicinal Chemistry Cell and Molecular Biology Aggregation mechanism Amyloid Driving forces Kinetic analysis Self-assembly |
description |
The aggregation of the amyloid-β (Aβ) peptide is linked to the pathogenesis of Alzheimer’s disease (AD). In particular, some point mutations within Aβ are associated with early-onset familial Alzheimer’s disease. Here we set out to explore how the physical properties of the altered side chains, including their sizes and charges, affect the molecular mechanisms of aggregation. We focus on Aβ42 with familial mutations—A21G (Flemish), E22K (Italian), E22G (Arctic), E22Q (Dutch), and D23N (Iowa)—which lead to similar or identical pathology with sporadic AD or severe cerebral amyloid angiopathy. Through global kinetic analysis, we find that for the E22K, E22G, E22Q, and D23N mutations, the acceleration of the overall aggregation originates primarily from the modulation of the nucleation processes, in particular secondary nucleation on the surface of existing fibrils, whereas the elongation process is not significantly affected. Remarkably, the D23 position appears to be responsible for most of the charge effects during nucleation, while the size of the side chain at the E22 position plays a more significant role than its charge. Thus, we have developed a kinetic approach to determine the nature and the magnitude of the contribution of specific residues to the rate of individual steps of the aggregation reaction, through targeted mutations and variations in ionic strength. This strategy can help rationalize the effect of some disease-related mutations as well as yield insights into the mechanism of aggregation and the transition states of the wild-type protein. |
format |
Article in Journal/Newspaper |
author |
Yang, Xiaoting Meisl, Georg Frohm, Birgitta Thulin, Eva Knowles, Tuomas P.J. Linse, Sara |
author_facet |
Yang, Xiaoting Meisl, Georg Frohm, Birgitta Thulin, Eva Knowles, Tuomas P.J. Linse, Sara |
author_sort |
Yang, Xiaoting |
title |
On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations |
title_short |
On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations |
title_full |
On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations |
title_fullStr |
On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations |
title_full_unstemmed |
On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations |
title_sort |
on the role of sidechain size and charge in the aggregation of aβ42 with familial mutations |
publisher |
National Academy of Sciences |
publishDate |
2018 |
url |
https://lup.lub.lu.se/record/cb6a140e-e66d-4113-82fc-59fbd5b5956f https://doi.org/10.1073/pnas.1803539115 |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Proceedings of the National Academy of Sciences of the United States of America; 115(26), pp 5849-5858 (2018) ISSN: 0027-8424 |
op_relation |
https://lup.lub.lu.se/record/cb6a140e-e66d-4113-82fc-59fbd5b5956f http://dx.doi.org/10.1073/pnas.1803539115 scopus:85049050338 pmid:29895690 |
op_doi |
https://doi.org/10.1073/pnas.1803539115 |
container_title |
Proceedings of the National Academy of Sciences |
container_volume |
115 |
container_issue |
26 |
container_start_page |
E5849 |
op_container_end_page |
E5858 |
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1799475633381703680 |