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Interference with Amyloid-β Nucleation by Transient Ligand Interaction
Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomer...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600523/ https://www.ncbi.nlm.nih.gov/pubmed/31195746 http://dx.doi.org/10.3390/molecules24112129 |
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author | Zhang, Tao Loschwitz, Jennifer Strodel, Birgit Nagel-Steger, Luitgard Willbold, Dieter |
author_facet | Zhang, Tao Loschwitz, Jennifer Strodel, Birgit Nagel-Steger, Luitgard Willbold, Dieter |
author_sort | Zhang, Tao |
collection | PubMed |
description | Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs. |
format | Online Article Text |
id | pubmed-6600523 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66005232019-07-16 Interference with Amyloid-β Nucleation by Transient Ligand Interaction Zhang, Tao Loschwitz, Jennifer Strodel, Birgit Nagel-Steger, Luitgard Willbold, Dieter Molecules Article Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs. MDPI 2019-06-05 /pmc/articles/PMC6600523/ /pubmed/31195746 http://dx.doi.org/10.3390/molecules24112129 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zhang, Tao Loschwitz, Jennifer Strodel, Birgit Nagel-Steger, Luitgard Willbold, Dieter Interference with Amyloid-β Nucleation by Transient Ligand Interaction |
title | Interference with Amyloid-β Nucleation by Transient Ligand Interaction |
title_full | Interference with Amyloid-β Nucleation by Transient Ligand Interaction |
title_fullStr | Interference with Amyloid-β Nucleation by Transient Ligand Interaction |
title_full_unstemmed | Interference with Amyloid-β Nucleation by Transient Ligand Interaction |
title_short | Interference with Amyloid-β Nucleation by Transient Ligand Interaction |
title_sort | interference with amyloid-β nucleation by transient ligand interaction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600523/ https://www.ncbi.nlm.nih.gov/pubmed/31195746 http://dx.doi.org/10.3390/molecules24112129 |
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