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Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain
Mutations in the ganglioside-induced differentiation associated protein 1 (GDAP1) cause severe peripheral motor and sensory neuropathies called Charcot-Marie-Tooth disease. GDAP1 expression induces fission of mitochondria and peroxisomes by a currently elusive mechanism, while disease causing mutati...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107993/ https://www.ncbi.nlm.nih.gov/pubmed/27841286 http://dx.doi.org/10.1038/srep36930 |
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author | Huber, Nina Bieniossek, Christoph Wagner, Konstanze Marion Elsässer, Hans-Peter Suter, Ueli Berger, Imre Niemann, Axel |
author_facet | Huber, Nina Bieniossek, Christoph Wagner, Konstanze Marion Elsässer, Hans-Peter Suter, Ueli Berger, Imre Niemann, Axel |
author_sort | Huber, Nina |
collection | PubMed |
description | Mutations in the ganglioside-induced differentiation associated protein 1 (GDAP1) cause severe peripheral motor and sensory neuropathies called Charcot-Marie-Tooth disease. GDAP1 expression induces fission of mitochondria and peroxisomes by a currently elusive mechanism, while disease causing mutations in GDAP1 impede the protein’s role in mitochondrial dynamics. In silico analysis reveals sequence similarities of GDAP1 to glutathione S-transferases (GSTs). However, a proof of GST activity and its possible impact on membrane dynamics are lacking to date. Using recombinant protein, we demonstrate for the first time theta-class-like GST activity for GDAP1, and it’s activity being regulated by the C-terminal hydrophobic domain 1 (HD1) of GDAP1 in an autoinhibitory manner. Moreover, we show that the HD1 amphipathic pattern is required to induce membrane dynamics by GDAP1. As both, fission and GST activities of GDAP1, are critically dependent on HD1, we propose that GDAP1 undergoes a molecular switch, turning from a pro-fission active to an auto-inhibited inactive conformation. |
format | Online Article Text |
id | pubmed-5107993 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-51079932016-11-22 Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain Huber, Nina Bieniossek, Christoph Wagner, Konstanze Marion Elsässer, Hans-Peter Suter, Ueli Berger, Imre Niemann, Axel Sci Rep Article Mutations in the ganglioside-induced differentiation associated protein 1 (GDAP1) cause severe peripheral motor and sensory neuropathies called Charcot-Marie-Tooth disease. GDAP1 expression induces fission of mitochondria and peroxisomes by a currently elusive mechanism, while disease causing mutations in GDAP1 impede the protein’s role in mitochondrial dynamics. In silico analysis reveals sequence similarities of GDAP1 to glutathione S-transferases (GSTs). However, a proof of GST activity and its possible impact on membrane dynamics are lacking to date. Using recombinant protein, we demonstrate for the first time theta-class-like GST activity for GDAP1, and it’s activity being regulated by the C-terminal hydrophobic domain 1 (HD1) of GDAP1 in an autoinhibitory manner. Moreover, we show that the HD1 amphipathic pattern is required to induce membrane dynamics by GDAP1. As both, fission and GST activities of GDAP1, are critically dependent on HD1, we propose that GDAP1 undergoes a molecular switch, turning from a pro-fission active to an auto-inhibited inactive conformation. Nature Publishing Group 2016-11-14 /pmc/articles/PMC5107993/ /pubmed/27841286 http://dx.doi.org/10.1038/srep36930 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Huber, Nina Bieniossek, Christoph Wagner, Konstanze Marion Elsässer, Hans-Peter Suter, Ueli Berger, Imre Niemann, Axel Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain |
title | Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain |
title_full | Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain |
title_fullStr | Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain |
title_full_unstemmed | Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain |
title_short | Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain |
title_sort | glutathione-conjugating and membrane-remodeling activity of gdap1 relies on amphipathic c-terminal domain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107993/ https://www.ncbi.nlm.nih.gov/pubmed/27841286 http://dx.doi.org/10.1038/srep36930 |
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