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

Abstract 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. Howeve...

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Autores principales:	Yuhei Tachi, Yuko Okamoto, Hisashi Okumura
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dd56961f09d24c21b1d253dd95928a15
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spelling	oai:doaj.org-article:dd56961f09d24c21b1d253dd95928a152021-12-02T15:09:53ZConformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster10.1038/s41598-019-43117-62045-2322https://doaj.org/article/dd56961f09d24c21b1d253dd95928a152019-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-43117-6https://doaj.org/toc/2045-2322Abstract 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.Yuhei TachiYuko OkamotoHisashi OkumuraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-11 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuhei Tachi Yuko Okamoto Hisashi Okumura Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster
description	Abstract 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.
format	article
author	Yuhei Tachi Yuko Okamoto Hisashi Okumura
author_facet	Yuhei Tachi Yuko Okamoto Hisashi Okumura
author_sort	Yuhei Tachi
title	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_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_sort	conformational change of amyloid-β 40 in association with binding to gm1-glycan cluster
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/dd56961f09d24c21b1d253dd95928a15
work_keys_str_mv	AT yuheitachi conformationalchangeofamyloidb40inassociationwithbindingtogm1glycancluster AT yukookamoto conformationalchangeofamyloidb40inassociationwithbindingtogm1glycancluster AT hisashiokumura conformationalchangeofamyloidb40inassociationwithbindingtogm1glycancluster
_version_	1718387784714027008

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

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