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Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features
Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptos...
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/PMC5686155/ https://www.ncbi.nlm.nih.gov/pubmed/29138502 http://dx.doi.org/10.1038/s41467-017-01701-2 |
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author | Pannek, Martin Simic, Zeljko Fuszard, Matthew Meleshin, Marat Rotili, Dante Mai, Antonello Schutkowski, Mike Steegborn, Clemens |
author_facet | Pannek, Martin Simic, Zeljko Fuszard, Matthew Meleshin, Marat Rotili, Dante Mai, Antonello Schutkowski, Mike Steegborn, Clemens |
author_sort | Pannek, Martin |
collection | PubMed |
description | Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4. The enzyme shows isoform-specific acyl selectivity, with significant activity against hydroxymethylglutarylation. Crystal structures of Sirt4 from Xenopus tropicalis reveal a particular acyl binding site with an additional access channel, rationalizing its activities. The structures further identify a conserved, isoform-specific Sirt4 loop that folds into the active site to potentially regulate catalysis. Using these results, we further establish efficient Sirt4 activity assays, an unusual Sirt4 regulation by NADH, and Sirt4 effects of pharmacological modulators. |
format | Online Article Text |
id | pubmed-5686155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56861552017-11-17 Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features Pannek, Martin Simic, Zeljko Fuszard, Matthew Meleshin, Marat Rotili, Dante Mai, Antonello Schutkowski, Mike Steegborn, Clemens Nat Commun Article Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4. The enzyme shows isoform-specific acyl selectivity, with significant activity against hydroxymethylglutarylation. Crystal structures of Sirt4 from Xenopus tropicalis reveal a particular acyl binding site with an additional access channel, rationalizing its activities. The structures further identify a conserved, isoform-specific Sirt4 loop that folds into the active site to potentially regulate catalysis. Using these results, we further establish efficient Sirt4 activity assays, an unusual Sirt4 regulation by NADH, and Sirt4 effects of pharmacological modulators. Nature Publishing Group UK 2017-11-15 /pmc/articles/PMC5686155/ /pubmed/29138502 http://dx.doi.org/10.1038/s41467-017-01701-2 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 Pannek, Martin Simic, Zeljko Fuszard, Matthew Meleshin, Marat Rotili, Dante Mai, Antonello Schutkowski, Mike Steegborn, Clemens Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features |
title | Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features |
title_full | Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features |
title_fullStr | Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features |
title_full_unstemmed | Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features |
title_short | Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features |
title_sort | crystal structures of the mitochondrial deacylase sirtuin 4 reveal isoform-specific acyl recognition and regulation features |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686155/ https://www.ncbi.nlm.nih.gov/pubmed/29138502 http://dx.doi.org/10.1038/s41467-017-01701-2 |
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