Cargando…
Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System
Polymerization into amyloid fibrils is a crucial step in the pathogenesis of neurodegenerative syndromes. Amyloid assembly is governed by properties of the sequence backbone and specific side-chain interactions, since fibrils from unrelated sequences possess similar structures and morphologies. Ther...
Autores principales: | , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2008
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265548/ https://www.ncbi.nlm.nih.gov/pubmed/18350169 http://dx.doi.org/10.1371/journal.pone.0001834 |
_version_ | 1782151492268982272 |
---|---|
author | Jean, Létitia Lee, Chiu Fan Shaw, Michael Vaux, David J. |
author_facet | Jean, Létitia Lee, Chiu Fan Shaw, Michael Vaux, David J. |
author_sort | Jean, Létitia |
collection | PubMed |
description | Polymerization into amyloid fibrils is a crucial step in the pathogenesis of neurodegenerative syndromes. Amyloid assembly is governed by properties of the sequence backbone and specific side-chain interactions, since fibrils from unrelated sequences possess similar structures and morphologies. Therefore, characterization of the structural determinants driving amyloid aggregation is of fundamental importance. We investigated the forces involved in the amyloid assembly of a model peptide derived from the oligomerization domain of acetylcholinesterase (AChE), AChE(586-599), through the effect of single point mutations on β-sheet propensity, conformation, fibrilization, surfactant activity, oligomerization and fibril morphology. AChE(586-599) was chosen due to its fibrilization tractability and AChE involvement in Alzheimer's disease. The results revealed how specific regions and residues can control AChE(586-599) assembly. Hydrophobic and/or aromatic residues were crucial for maintaining a high β-strand propensity, for the conformational transition to β-sheet, and for the first stage of aggregation. We also demonstrated that positively charged side-chains might be involved in electrostatic interactions, which could control the transition to β-sheet, the oligomerization and assembly stability. Further interactions were also found to participate in the assembly. We showed that some residues were important for AChE(586-599) surfactant activity and that amyloid assembly might preferentially occur at an air-water interface. Consistently with the experimental observations and assembly models for other amyloid systems, we propose a model for AChE(586-599) assembly in which a steric-zipper formed through specific interactions (hydrophobic, electrostatic, cation-π, SH-aromatic, metal chelation and polar-polar) would maintain the β-sheets together. We also propose that the stacking between the strands in the β-sheets along the fiber axis could be stabilized through π-π interactions and metal chelation. The dissection of the specific molecular recognition driving AChE(586-599) amyloid assembly has provided further knowledge on such poorly understood and complicated process, which could be applied to protein folding and the targeting of amyloid diseases. |
format | Text |
id | pubmed-2265548 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-22655482008-03-19 Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System Jean, Létitia Lee, Chiu Fan Shaw, Michael Vaux, David J. PLoS One Research Article Polymerization into amyloid fibrils is a crucial step in the pathogenesis of neurodegenerative syndromes. Amyloid assembly is governed by properties of the sequence backbone and specific side-chain interactions, since fibrils from unrelated sequences possess similar structures and morphologies. Therefore, characterization of the structural determinants driving amyloid aggregation is of fundamental importance. We investigated the forces involved in the amyloid assembly of a model peptide derived from the oligomerization domain of acetylcholinesterase (AChE), AChE(586-599), through the effect of single point mutations on β-sheet propensity, conformation, fibrilization, surfactant activity, oligomerization and fibril morphology. AChE(586-599) was chosen due to its fibrilization tractability and AChE involvement in Alzheimer's disease. The results revealed how specific regions and residues can control AChE(586-599) assembly. Hydrophobic and/or aromatic residues were crucial for maintaining a high β-strand propensity, for the conformational transition to β-sheet, and for the first stage of aggregation. We also demonstrated that positively charged side-chains might be involved in electrostatic interactions, which could control the transition to β-sheet, the oligomerization and assembly stability. Further interactions were also found to participate in the assembly. We showed that some residues were important for AChE(586-599) surfactant activity and that amyloid assembly might preferentially occur at an air-water interface. Consistently with the experimental observations and assembly models for other amyloid systems, we propose a model for AChE(586-599) assembly in which a steric-zipper formed through specific interactions (hydrophobic, electrostatic, cation-π, SH-aromatic, metal chelation and polar-polar) would maintain the β-sheets together. We also propose that the stacking between the strands in the β-sheets along the fiber axis could be stabilized through π-π interactions and metal chelation. The dissection of the specific molecular recognition driving AChE(586-599) amyloid assembly has provided further knowledge on such poorly understood and complicated process, which could be applied to protein folding and the targeting of amyloid diseases. Public Library of Science 2008-03-19 /pmc/articles/PMC2265548/ /pubmed/18350169 http://dx.doi.org/10.1371/journal.pone.0001834 Text en Jean et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Jean, Létitia Lee, Chiu Fan Shaw, Michael Vaux, David J. Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System |
title | Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System |
title_full | Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System |
title_fullStr | Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System |
title_full_unstemmed | Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System |
title_short | Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System |
title_sort | structural elements regulating amyloidogenesis: a cholinesterase model system |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265548/ https://www.ncbi.nlm.nih.gov/pubmed/18350169 http://dx.doi.org/10.1371/journal.pone.0001834 |
work_keys_str_mv | AT jeanletitia structuralelementsregulatingamyloidogenesisacholinesterasemodelsystem AT leechiufan structuralelementsregulatingamyloidogenesisacholinesterasemodelsystem AT shawmichael structuralelementsregulatingamyloidogenesisacholinesterasemodelsystem AT vauxdavidj structuralelementsregulatingamyloidogenesisacholinesterasemodelsystem |