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The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease
Lon is an essential, multitasking AAA(+) protease regulating many cellular processes in species across all kingdoms of life. Altered expression levels of the human mitochondrial Lon protease (hLon) are linked to serious diseases including myopathies, paraplegia, and cancer. Here, we present the firs...
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/PMC5025710/ https://www.ncbi.nlm.nih.gov/pubmed/27632940 http://dx.doi.org/10.1038/srep33631 |
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author | Kereïche, Sami Kováčik, Lubomír Bednár, Jan Pevala, Vladimír Kunová, Nina Ondrovičová, Gabriela Bauer, Jacob Ambro, Ľuboš Bellová, Jana Kutejová, Eva Raška, Ivan |
author_facet | Kereïche, Sami Kováčik, Lubomír Bednár, Jan Pevala, Vladimír Kunová, Nina Ondrovičová, Gabriela Bauer, Jacob Ambro, Ľuboš Bellová, Jana Kutejová, Eva Raška, Ivan |
author_sort | Kereïche, Sami |
collection | PubMed |
description | Lon is an essential, multitasking AAA(+) protease regulating many cellular processes in species across all kingdoms of life. Altered expression levels of the human mitochondrial Lon protease (hLon) are linked to serious diseases including myopathies, paraplegia, and cancer. Here, we present the first 3D structure of full-length hLon using cryo-electron microscopy. hLon has a unique three-dimensional structure, in which the proteolytic and ATP-binding domains (AP-domain) form a hexameric chamber, while the N-terminal domain is arranged as a trimer of dimers. These two domains are linked by a narrow trimeric channel composed likely of coiled-coil helices. In the presence of AMP-PNP, the AP-domain has a closed-ring conformation and its N-terminal entry gate appears closed, but in ADP binding, it switches to a lock-washer conformation and its N-terminal gate opens, which is accompanied by a rearrangement of the N-terminal domain. We have also found that both the enzymatic activities and the 3D structure of a hLon mutant lacking the first 156 amino acids are severely disturbed, showing that hLon’s N-terminal domains are crucial for the overall structure of the hLon, maintaining a conformation allowing its proper functioning. |
format | Online Article Text |
id | pubmed-5025710 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50257102016-09-22 The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease Kereïche, Sami Kováčik, Lubomír Bednár, Jan Pevala, Vladimír Kunová, Nina Ondrovičová, Gabriela Bauer, Jacob Ambro, Ľuboš Bellová, Jana Kutejová, Eva Raška, Ivan Sci Rep Article Lon is an essential, multitasking AAA(+) protease regulating many cellular processes in species across all kingdoms of life. Altered expression levels of the human mitochondrial Lon protease (hLon) are linked to serious diseases including myopathies, paraplegia, and cancer. Here, we present the first 3D structure of full-length hLon using cryo-electron microscopy. hLon has a unique three-dimensional structure, in which the proteolytic and ATP-binding domains (AP-domain) form a hexameric chamber, while the N-terminal domain is arranged as a trimer of dimers. These two domains are linked by a narrow trimeric channel composed likely of coiled-coil helices. In the presence of AMP-PNP, the AP-domain has a closed-ring conformation and its N-terminal entry gate appears closed, but in ADP binding, it switches to a lock-washer conformation and its N-terminal gate opens, which is accompanied by a rearrangement of the N-terminal domain. We have also found that both the enzymatic activities and the 3D structure of a hLon mutant lacking the first 156 amino acids are severely disturbed, showing that hLon’s N-terminal domains are crucial for the overall structure of the hLon, maintaining a conformation allowing its proper functioning. Nature Publishing Group 2016-09-16 /pmc/articles/PMC5025710/ /pubmed/27632940 http://dx.doi.org/10.1038/srep33631 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 Kereïche, Sami Kováčik, Lubomír Bednár, Jan Pevala, Vladimír Kunová, Nina Ondrovičová, Gabriela Bauer, Jacob Ambro, Ľuboš Bellová, Jana Kutejová, Eva Raška, Ivan The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease |
title | The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease |
title_full | The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease |
title_fullStr | The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease |
title_full_unstemmed | The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease |
title_short | The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease |
title_sort | n-terminal domain plays a crucial role in the structure of a full-length human mitochondrial lon protease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025710/ https://www.ncbi.nlm.nih.gov/pubmed/27632940 http://dx.doi.org/10.1038/srep33631 |
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