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The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex

Alzheimer’s disease is the most common progressive neurodegenerative disorder and is characterized by the presence of amyloid β (Aβ) plaques in the brain. The γ-secretase complex, which produces Aβ, is an intramembrane-cleaving protease consisting of four membrane proteins. In this paper we investig...

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Autores principales: Orzeł, Urszula, Jakowiecki, Jakub, Młynarczyk, Krzysztof, Filipek, Sławomir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301813/
https://www.ncbi.nlm.nih.gov/pubmed/34202467
http://dx.doi.org/10.3390/biom11070935
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author Orzeł, Urszula
Jakowiecki, Jakub
Młynarczyk, Krzysztof
Filipek, Sławomir
author_facet Orzeł, Urszula
Jakowiecki, Jakub
Młynarczyk, Krzysztof
Filipek, Sławomir
author_sort Orzeł, Urszula
collection PubMed
description Alzheimer’s disease is the most common progressive neurodegenerative disorder and is characterized by the presence of amyloid β (Aβ) plaques in the brain. The γ-secretase complex, which produces Aβ, is an intramembrane-cleaving protease consisting of four membrane proteins. In this paper we investigated the amyloidogenic fragments of amyloid precursor protein (substrates Aβ(43) and Aβ(45), leading to less amyloidogenic Aβ(40) and more amyloidogenic Aβ(42), respectively) docked to the binding site of presenilin, the catalytic subunit of γ-secretase. In total, we performed 9 μs of all-atom molecular dynamics simulations of the whole γ-secretase complex with both substrates in low (10%) and high (50%) concentrations of cholesterol in the membrane. We found that, at the high cholesterol level, the Aβ(45) helix was statistically more flexible in the binding site of presenilin than Aβ(43). An increase in the cholesterol concentration was also correlated with a higher flexibility of the Aβ(45) helix, which suggests incompatibility between Aβ(45) and the binding site of presenilin potentiated by a high cholesterol level. However, at the C-terminal part of Aβ(45), the active site of presenilin was more compact in the case of a high cholesterol level, which could promote processing of this substrate. We also performed detailed mapping of the cholesterol binding sites at low and high cholesterol concentrations, which were independent of the typical cholesterol binding motifs.
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spelling pubmed-83018132021-07-24 The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex Orzeł, Urszula Jakowiecki, Jakub Młynarczyk, Krzysztof Filipek, Sławomir Biomolecules Article Alzheimer’s disease is the most common progressive neurodegenerative disorder and is characterized by the presence of amyloid β (Aβ) plaques in the brain. The γ-secretase complex, which produces Aβ, is an intramembrane-cleaving protease consisting of four membrane proteins. In this paper we investigated the amyloidogenic fragments of amyloid precursor protein (substrates Aβ(43) and Aβ(45), leading to less amyloidogenic Aβ(40) and more amyloidogenic Aβ(42), respectively) docked to the binding site of presenilin, the catalytic subunit of γ-secretase. In total, we performed 9 μs of all-atom molecular dynamics simulations of the whole γ-secretase complex with both substrates in low (10%) and high (50%) concentrations of cholesterol in the membrane. We found that, at the high cholesterol level, the Aβ(45) helix was statistically more flexible in the binding site of presenilin than Aβ(43). An increase in the cholesterol concentration was also correlated with a higher flexibility of the Aβ(45) helix, which suggests incompatibility between Aβ(45) and the binding site of presenilin potentiated by a high cholesterol level. However, at the C-terminal part of Aβ(45), the active site of presenilin was more compact in the case of a high cholesterol level, which could promote processing of this substrate. We also performed detailed mapping of the cholesterol binding sites at low and high cholesterol concentrations, which were independent of the typical cholesterol binding motifs. MDPI 2021-06-24 /pmc/articles/PMC8301813/ /pubmed/34202467 http://dx.doi.org/10.3390/biom11070935 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Orzeł, Urszula
Jakowiecki, Jakub
Młynarczyk, Krzysztof
Filipek, Sławomir
The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex
title The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex
title_full The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex
title_fullStr The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex
title_full_unstemmed The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex
title_short The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex
title_sort role of cholesterol in amyloidogenic substrate binding to the γ-secretase complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301813/
https://www.ncbi.nlm.nih.gov/pubmed/34202467
http://dx.doi.org/10.3390/biom11070935
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