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Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster

Aggregates of amyloid-β (Aβ) peptide are well known to be the causative substance of Alzheimer’s disease (AD). Recent studies showed that monosialotetrahexosylganglioside (GM1) clusters induce the pathological aggregation of Aβ peptide responsible for the onset and development of AD. However, the ef...

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Autores principales: Tachi, Yuhei, Okamoto, Yuko, Okumura, Hisashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497634/
https://www.ncbi.nlm.nih.gov/pubmed/31048748
http://dx.doi.org/10.1038/s41598-019-43117-6
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author Tachi, Yuhei
Okamoto, Yuko
Okumura, Hisashi
author_facet Tachi, Yuhei
Okamoto, Yuko
Okumura, Hisashi
author_sort Tachi, Yuhei
collection PubMed
description Aggregates of amyloid-β (Aβ) peptide are well known to be the causative substance of Alzheimer’s disease (AD). Recent studies showed that monosialotetrahexosylganglioside (GM1) clusters induce the pathological aggregation of Aβ peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on Aβ conformations has yet to be clarified. Interactions between Aβ peptide and GM1-glycan cluster is important for the earliest stage of the toxic aggregation on GM1 cluster. Here, we performed all-atom molecular dynamics (MD) simulations of Aβ40 on a recently developed artificial GM1-glycan cluster. The artificial GM1-glycan cluster facilitates the characterization of interactions between Aβ40 and multiple GM1-glycans. We succeeded in observing the binding of Aβ40 to the GM1-glycan cluster in all of our MD simulations. Results obtained from these MD simulations indicate the importance of HHQ (13-15) segment of Aβ40 for the GM1-glycan cluster recognition. This result is consistent with previous experimental studies regarding the glycan recognition of Aβ peptide. The recognition mechanism of HHQ (13-15) segment is mainly explained by non-specific stacking interactions between side-chains of histidine and rings of sugar residues, in which the HHQ regime forms coil and bend structures. Moreover, we found that Aβ40 exhibits helix structures at C-terminal side on the GM1-glycan cluster. The helix formation is the initial stage of the pathological aggregation at ceramide moieties of GM1 cluster. The binding of Lys28 to Neu triggers the helix formation at C-terminus side because the formation of a salt bridge between Lys28 and Neu leads to change of intrachain interactions of Aβ40. Our findings suggest that the pathological helix formation of Aβ40 is initiated at GM1-glycan moieties rather than lipid ceramide moieties.
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spelling pubmed-64976342019-05-17 Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster Tachi, Yuhei Okamoto, Yuko Okumura, Hisashi Sci Rep Article Aggregates of amyloid-β (Aβ) peptide are well known to be the causative substance of Alzheimer’s disease (AD). Recent studies showed that monosialotetrahexosylganglioside (GM1) clusters induce the pathological aggregation of Aβ peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on Aβ conformations has yet to be clarified. Interactions between Aβ peptide and GM1-glycan cluster is important for the earliest stage of the toxic aggregation on GM1 cluster. Here, we performed all-atom molecular dynamics (MD) simulations of Aβ40 on a recently developed artificial GM1-glycan cluster. The artificial GM1-glycan cluster facilitates the characterization of interactions between Aβ40 and multiple GM1-glycans. We succeeded in observing the binding of Aβ40 to the GM1-glycan cluster in all of our MD simulations. Results obtained from these MD simulations indicate the importance of HHQ (13-15) segment of Aβ40 for the GM1-glycan cluster recognition. This result is consistent with previous experimental studies regarding the glycan recognition of Aβ peptide. The recognition mechanism of HHQ (13-15) segment is mainly explained by non-specific stacking interactions between side-chains of histidine and rings of sugar residues, in which the HHQ regime forms coil and bend structures. Moreover, we found that Aβ40 exhibits helix structures at C-terminal side on the GM1-glycan cluster. The helix formation is the initial stage of the pathological aggregation at ceramide moieties of GM1 cluster. The binding of Lys28 to Neu triggers the helix formation at C-terminus side because the formation of a salt bridge between Lys28 and Neu leads to change of intrachain interactions of Aβ40. Our findings suggest that the pathological helix formation of Aβ40 is initiated at GM1-glycan moieties rather than lipid ceramide moieties. Nature Publishing Group UK 2019-05-02 /pmc/articles/PMC6497634/ /pubmed/31048748 http://dx.doi.org/10.1038/s41598-019-43117-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Tachi, Yuhei
Okamoto, Yuko
Okumura, Hisashi
Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster
title Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster
title_full Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster
title_fullStr Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster
title_full_unstemmed Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster
title_short Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster
title_sort conformational change of amyloid-β 40 in association with binding to gm1-glycan cluster
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497634/
https://www.ncbi.nlm.nih.gov/pubmed/31048748
http://dx.doi.org/10.1038/s41598-019-43117-6
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