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The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation
Immunoglobulin light chain-derived (AL) amyloidosis is a debilitating disease without known cure. Almost nothing is known about the structural factors driving the amyloidogenesis of the light chains. This study aimed to identify the fibrillogenic hotspots of the model protein 6aJL2 and in pursuing t...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395779/ https://www.ncbi.nlm.nih.gov/pubmed/30816248 http://dx.doi.org/10.1038/s41598-019-39781-3 |
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author | Ruiz-Zamora, Robin Axel Guillaumé, Simon Al-Hilaly, Youssra K. Al-Garawi, Zahraa Rodríguez-Alvarez, Francisco Javier Zavala-Padilla, Guadalupe Pérez-Carreón, Julio I. Rodríguez-Ambriz, Sandra L. Herrera, Guillermo A. Becerril-Luján, Baltazar Ochoa-Leyva, Adrián Melendez-Zajgla, Jorge Serpell, Louise del Pozo-Yauner, Luis |
author_facet | Ruiz-Zamora, Robin Axel Guillaumé, Simon Al-Hilaly, Youssra K. Al-Garawi, Zahraa Rodríguez-Alvarez, Francisco Javier Zavala-Padilla, Guadalupe Pérez-Carreón, Julio I. Rodríguez-Ambriz, Sandra L. Herrera, Guillermo A. Becerril-Luján, Baltazar Ochoa-Leyva, Adrián Melendez-Zajgla, Jorge Serpell, Louise del Pozo-Yauner, Luis |
author_sort | Ruiz-Zamora, Robin Axel |
collection | PubMed |
description | Immunoglobulin light chain-derived (AL) amyloidosis is a debilitating disease without known cure. Almost nothing is known about the structural factors driving the amyloidogenesis of the light chains. This study aimed to identify the fibrillogenic hotspots of the model protein 6aJL2 and in pursuing this goal, two complementary approaches were applied. One of them was based on several web-based computational tools optimized to predict fibrillogenic/aggregation-prone sequences based on different structural and biophysical properties of the polypeptide chain. Then, the predictions were confirmed with an ad-hoc synthetic peptide library. In the second approach, 6aJL2 protein was proteolyzed with trypsin, and the products incubated in aggregation-promoting conditions. Then, the aggregation-prone fragments were identified by combining standard proteomic methods, and the results validated with a set of synthetic peptides with the sequence of the tryptic fragments. Both strategies coincided to identify a fibrillogenic hotspot located at the CDR1 and β-strand C of the protein, which was confirmed by scanning proline mutagenesis analysis. However, only the proteolysis-based strategy revealed additional fibrillogenic hotspots in two other regions of the protein. It was shown that a fibrillogenic hotspot associated to the CDR1 is also encoded by several κ and λ germline variable domain gene segments. Some parts of this study have been included in the chapter “The Structural Determinants of the Immunoglobulin Light Chain Amyloid Aggregation”, published in Physical Biology of Proteins and Peptides, Springer 2015 (ISBN 978-3-319-21687-4). |
format | Online Article Text |
id | pubmed-6395779 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63957792019-03-05 The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation Ruiz-Zamora, Robin Axel Guillaumé, Simon Al-Hilaly, Youssra K. Al-Garawi, Zahraa Rodríguez-Alvarez, Francisco Javier Zavala-Padilla, Guadalupe Pérez-Carreón, Julio I. Rodríguez-Ambriz, Sandra L. Herrera, Guillermo A. Becerril-Luján, Baltazar Ochoa-Leyva, Adrián Melendez-Zajgla, Jorge Serpell, Louise del Pozo-Yauner, Luis Sci Rep Article Immunoglobulin light chain-derived (AL) amyloidosis is a debilitating disease without known cure. Almost nothing is known about the structural factors driving the amyloidogenesis of the light chains. This study aimed to identify the fibrillogenic hotspots of the model protein 6aJL2 and in pursuing this goal, two complementary approaches were applied. One of them was based on several web-based computational tools optimized to predict fibrillogenic/aggregation-prone sequences based on different structural and biophysical properties of the polypeptide chain. Then, the predictions were confirmed with an ad-hoc synthetic peptide library. In the second approach, 6aJL2 protein was proteolyzed with trypsin, and the products incubated in aggregation-promoting conditions. Then, the aggregation-prone fragments were identified by combining standard proteomic methods, and the results validated with a set of synthetic peptides with the sequence of the tryptic fragments. Both strategies coincided to identify a fibrillogenic hotspot located at the CDR1 and β-strand C of the protein, which was confirmed by scanning proline mutagenesis analysis. However, only the proteolysis-based strategy revealed additional fibrillogenic hotspots in two other regions of the protein. It was shown that a fibrillogenic hotspot associated to the CDR1 is also encoded by several κ and λ germline variable domain gene segments. Some parts of this study have been included in the chapter “The Structural Determinants of the Immunoglobulin Light Chain Amyloid Aggregation”, published in Physical Biology of Proteins and Peptides, Springer 2015 (ISBN 978-3-319-21687-4). Nature Publishing Group UK 2019-02-28 /pmc/articles/PMC6395779/ /pubmed/30816248 http://dx.doi.org/10.1038/s41598-019-39781-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Ruiz-Zamora, Robin Axel Guillaumé, Simon Al-Hilaly, Youssra K. Al-Garawi, Zahraa Rodríguez-Alvarez, Francisco Javier Zavala-Padilla, Guadalupe Pérez-Carreón, Julio I. Rodríguez-Ambriz, Sandra L. Herrera, Guillermo A. Becerril-Luján, Baltazar Ochoa-Leyva, Adrián Melendez-Zajgla, Jorge Serpell, Louise del Pozo-Yauner, Luis The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation |
title | The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation |
title_full | The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation |
title_fullStr | The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation |
title_full_unstemmed | The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation |
title_short | The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation |
title_sort | cdr1 and other regions of immunoglobulin light chains are hot spots for amyloid aggregation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395779/ https://www.ncbi.nlm.nih.gov/pubmed/30816248 http://dx.doi.org/10.1038/s41598-019-39781-3 |
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