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Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release
Low pH-induced ligand release and receptor recycling are important steps for endocytosis. The transmembrane protein sortilin, a β-propeller containing endocytosis receptor, internalizes a diverse set of ligands with roles in cell differentiation and homeostasis. The molecular mechanisms of pH-mediat...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700061/ https://www.ncbi.nlm.nih.gov/pubmed/29167428 http://dx.doi.org/10.1038/s41467-017-01485-5 |
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author | Leloup, Nadia Lössl, Philip Meijer, Dimphna H. Brennich, Martha Heck, Albert J. R. Thies-Weesie, Dominique M. E. Janssen, Bert J. C. |
author_facet | Leloup, Nadia Lössl, Philip Meijer, Dimphna H. Brennich, Martha Heck, Albert J. R. Thies-Weesie, Dominique M. E. Janssen, Bert J. C. |
author_sort | Leloup, Nadia |
collection | PubMed |
description | Low pH-induced ligand release and receptor recycling are important steps for endocytosis. The transmembrane protein sortilin, a β-propeller containing endocytosis receptor, internalizes a diverse set of ligands with roles in cell differentiation and homeostasis. The molecular mechanisms of pH-mediated ligand release and sortilin recycling are unresolved. Here we present crystal structures that show the sortilin luminal segment (s-sortilin) undergoes a conformational change and dimerizes at low pH. The conformational change, within all three sortilin luminal domains, provides an altered surface and the dimers sterically shield a large interface while bringing the two s-sortilin C-termini into close proximity. Biophysical and cell-based assays show that members of two different ligand families, (pro)neurotrophins and neurotensin, preferentially bind the sortilin monomer. This indicates that sortilin dimerization and conformational change discharges ligands and triggers recycling. More generally, this work may reveal a double mechanism for low pH-induced ligand release by endocytosis receptors. |
format | Online Article Text |
id | pubmed-5700061 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57000612017-11-24 Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release Leloup, Nadia Lössl, Philip Meijer, Dimphna H. Brennich, Martha Heck, Albert J. R. Thies-Weesie, Dominique M. E. Janssen, Bert J. C. Nat Commun Article Low pH-induced ligand release and receptor recycling are important steps for endocytosis. The transmembrane protein sortilin, a β-propeller containing endocytosis receptor, internalizes a diverse set of ligands with roles in cell differentiation and homeostasis. The molecular mechanisms of pH-mediated ligand release and sortilin recycling are unresolved. Here we present crystal structures that show the sortilin luminal segment (s-sortilin) undergoes a conformational change and dimerizes at low pH. The conformational change, within all three sortilin luminal domains, provides an altered surface and the dimers sterically shield a large interface while bringing the two s-sortilin C-termini into close proximity. Biophysical and cell-based assays show that members of two different ligand families, (pro)neurotrophins and neurotensin, preferentially bind the sortilin monomer. This indicates that sortilin dimerization and conformational change discharges ligands and triggers recycling. More generally, this work may reveal a double mechanism for low pH-induced ligand release by endocytosis receptors. Nature Publishing Group UK 2017-11-22 /pmc/articles/PMC5700061/ /pubmed/29167428 http://dx.doi.org/10.1038/s41467-017-01485-5 Text en © The Author(s) 2017 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 Leloup, Nadia Lössl, Philip Meijer, Dimphna H. Brennich, Martha Heck, Albert J. R. Thies-Weesie, Dominique M. E. Janssen, Bert J. C. Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release |
title | Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release |
title_full | Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release |
title_fullStr | Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release |
title_full_unstemmed | Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release |
title_short | Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release |
title_sort | low ph-induced conformational change and dimerization of sortilin triggers endocytosed ligand release |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700061/ https://www.ncbi.nlm.nih.gov/pubmed/29167428 http://dx.doi.org/10.1038/s41467-017-01485-5 |
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