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Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins
Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-j...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933289/ https://www.ncbi.nlm.nih.gov/pubmed/29780459 http://dx.doi.org/10.1039/c8sc00166a |
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author | Malgieri, Gaetano D'Abrosca, Gianluca Pirone, Luciano Toto, Angelo Palmieri, Maddalena Russo, Luigi Sciacca, Michele Francesco Maria Tatè, Rosarita Sivo, Valeria Baglivo, Ilaria Majewska, Roksana Coletta, Massimo Pedone, Paolo Vincenzo Isernia, Carla De Stefano, Mario Gianni, Stefano Pedone, Emilia Maria Milardi, Danilo Fattorusso, Roberto |
author_facet | Malgieri, Gaetano D'Abrosca, Gianluca Pirone, Luciano Toto, Angelo Palmieri, Maddalena Russo, Luigi Sciacca, Michele Francesco Maria Tatè, Rosarita Sivo, Valeria Baglivo, Ilaria Majewska, Roksana Coletta, Massimo Pedone, Paolo Vincenzo Isernia, Carla De Stefano, Mario Gianni, Stefano Pedone, Emilia Maria Milardi, Danilo Fattorusso, Roberto |
author_sort | Malgieri, Gaetano |
collection | PubMed |
description | Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml1(53–149) and zinc-lacking Ml4(52–151). The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms. Particularly, Ros87 and Ml1(53–149) appear to be much more stable to guanidine denaturation and are characterized by folding mechanisms including the presence of an intermediate. On the other hand, metal lacking Ml4(52–151) folds according to a classic two-state model. Successively, we have monitored the capabilities of Ros87, Ml4(52–151) and Ml1(53–149) to form amyloid fibrils under native conditions. Particularly, we show, by CD, fluorescence, DLS, TEM and SEM experiments, that after 168 hours, amyloid formation of Ros87 has started, while Ml1(53–149) has formed only amorphous aggregates and Ml4(52–151) is still monomeric in solution. This study shows how metal binding can influence protein folding pathways and thereby control conformational accessibility to aggregation-prone states, which in turn changes aggregation kinetics, shedding light on the role of metal ions in the development of protein deposition diseases. |
format | Online Article Text |
id | pubmed-5933289 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-59332892018-05-18 Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins Malgieri, Gaetano D'Abrosca, Gianluca Pirone, Luciano Toto, Angelo Palmieri, Maddalena Russo, Luigi Sciacca, Michele Francesco Maria Tatè, Rosarita Sivo, Valeria Baglivo, Ilaria Majewska, Roksana Coletta, Massimo Pedone, Paolo Vincenzo Isernia, Carla De Stefano, Mario Gianni, Stefano Pedone, Emilia Maria Milardi, Danilo Fattorusso, Roberto Chem Sci Chemistry Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml1(53–149) and zinc-lacking Ml4(52–151). The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms. Particularly, Ros87 and Ml1(53–149) appear to be much more stable to guanidine denaturation and are characterized by folding mechanisms including the presence of an intermediate. On the other hand, metal lacking Ml4(52–151) folds according to a classic two-state model. Successively, we have monitored the capabilities of Ros87, Ml4(52–151) and Ml1(53–149) to form amyloid fibrils under native conditions. Particularly, we show, by CD, fluorescence, DLS, TEM and SEM experiments, that after 168 hours, amyloid formation of Ros87 has started, while Ml1(53–149) has formed only amorphous aggregates and Ml4(52–151) is still monomeric in solution. This study shows how metal binding can influence protein folding pathways and thereby control conformational accessibility to aggregation-prone states, which in turn changes aggregation kinetics, shedding light on the role of metal ions in the development of protein deposition diseases. Royal Society of Chemistry 2018-03-01 /pmc/articles/PMC5933289/ /pubmed/29780459 http://dx.doi.org/10.1039/c8sc00166a Text en This journal is © The Royal Society of Chemistry 2018 http://creativecommons.org/licenses/by/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) |
spellingShingle | Chemistry Malgieri, Gaetano D'Abrosca, Gianluca Pirone, Luciano Toto, Angelo Palmieri, Maddalena Russo, Luigi Sciacca, Michele Francesco Maria Tatè, Rosarita Sivo, Valeria Baglivo, Ilaria Majewska, Roksana Coletta, Massimo Pedone, Paolo Vincenzo Isernia, Carla De Stefano, Mario Gianni, Stefano Pedone, Emilia Maria Milardi, Danilo Fattorusso, Roberto Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins |
title | Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins
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title_full | Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins
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title_fullStr | Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins
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title_full_unstemmed | Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins
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title_short | Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins
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title_sort | folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933289/ https://www.ncbi.nlm.nih.gov/pubmed/29780459 http://dx.doi.org/10.1039/c8sc00166a |
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