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Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy
The digestion of gluten generates toxic peptides, among which a highly immunogenic proline-rich 33-mer from wheat α-gliadin, that trigger coeliac disease. Neprosin from the pitcher plant is a reported prolyl endopeptidase. Here, we produce recombinant neprosin and its mutants, and find that full-len...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343461/ https://www.ncbi.nlm.nih.gov/pubmed/35915115 http://dx.doi.org/10.1038/s41467-022-32215-1 |
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author | del Amo-Maestro, Laura Mendes, Soraia R. Rodríguez-Banqueri, Arturo Garzon-Flores, Laura Girbal, Marina Rodríguez-Lagunas, María José Guevara, Tibisay Franch, Àngels Pérez-Cano, Francisco J. Eckhard, Ulrich Gomis-Rüth, F. Xavier |
author_facet | del Amo-Maestro, Laura Mendes, Soraia R. Rodríguez-Banqueri, Arturo Garzon-Flores, Laura Girbal, Marina Rodríguez-Lagunas, María José Guevara, Tibisay Franch, Àngels Pérez-Cano, Francisco J. Eckhard, Ulrich Gomis-Rüth, F. Xavier |
author_sort | del Amo-Maestro, Laura |
collection | PubMed |
description | The digestion of gluten generates toxic peptides, among which a highly immunogenic proline-rich 33-mer from wheat α-gliadin, that trigger coeliac disease. Neprosin from the pitcher plant is a reported prolyl endopeptidase. Here, we produce recombinant neprosin and its mutants, and find that full-length neprosin is a zymogen, which is self-activated at gastric pH by the release of an all-β pro-domain via a pH-switch mechanism featuring a lysine plug. The catalytic domain is an atypical 7+8-stranded β-sandwich with an extended active-site cleft containing an unprecedented pair of catalytic glutamates. Neprosin efficiently degrades both gliadin and the 33-mer in vitro under gastric conditions and is reversibly inactivated at pH > 5. Moreover, co-administration of gliadin and the neprosin zymogen at the ratio 500:1 reduces the abundance of the 33-mer in the small intestine of mice by up to 90%. Neprosin therefore founds a family of eukaryotic glutamate endopeptidases that fulfils requisites for a therapeutic glutenase. |
format | Online Article Text |
id | pubmed-9343461 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93434612022-08-03 Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy del Amo-Maestro, Laura Mendes, Soraia R. Rodríguez-Banqueri, Arturo Garzon-Flores, Laura Girbal, Marina Rodríguez-Lagunas, María José Guevara, Tibisay Franch, Àngels Pérez-Cano, Francisco J. Eckhard, Ulrich Gomis-Rüth, F. Xavier Nat Commun Article The digestion of gluten generates toxic peptides, among which a highly immunogenic proline-rich 33-mer from wheat α-gliadin, that trigger coeliac disease. Neprosin from the pitcher plant is a reported prolyl endopeptidase. Here, we produce recombinant neprosin and its mutants, and find that full-length neprosin is a zymogen, which is self-activated at gastric pH by the release of an all-β pro-domain via a pH-switch mechanism featuring a lysine plug. The catalytic domain is an atypical 7+8-stranded β-sandwich with an extended active-site cleft containing an unprecedented pair of catalytic glutamates. Neprosin efficiently degrades both gliadin and the 33-mer in vitro under gastric conditions and is reversibly inactivated at pH > 5. Moreover, co-administration of gliadin and the neprosin zymogen at the ratio 500:1 reduces the abundance of the 33-mer in the small intestine of mice by up to 90%. Neprosin therefore founds a family of eukaryotic glutamate endopeptidases that fulfils requisites for a therapeutic glutenase. Nature Publishing Group UK 2022-08-01 /pmc/articles/PMC9343461/ /pubmed/35915115 http://dx.doi.org/10.1038/s41467-022-32215-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article del Amo-Maestro, Laura Mendes, Soraia R. Rodríguez-Banqueri, Arturo Garzon-Flores, Laura Girbal, Marina Rodríguez-Lagunas, María José Guevara, Tibisay Franch, Àngels Pérez-Cano, Francisco J. Eckhard, Ulrich Gomis-Rüth, F. Xavier Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy |
title | Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy |
title_full | Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy |
title_fullStr | Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy |
title_full_unstemmed | Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy |
title_short | Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy |
title_sort | molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343461/ https://www.ncbi.nlm.nih.gov/pubmed/35915115 http://dx.doi.org/10.1038/s41467-022-32215-1 |
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