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Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6
The E1 enzyme Uba6 initiates signal transduction by activating ubiquitin and the ubiquitin-like protein FAT10 in a two-step process involving sequential catalysis of adenylation and thioester bond formation. To gain mechanistic insights into these processes, we determined the crystal structure of a...
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/PMC9391358/ https://www.ncbi.nlm.nih.gov/pubmed/35986001 http://dx.doi.org/10.1038/s41467-022-32613-5 |
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author | Yuan, Lingmin Gao, Fei Lv, Zongyang Nayak, Digant Nayak, Anindita Santos Bury, Priscila dos Cano, Kristin E. Jia, Lijia Oleinik, Natalia Atilgan, Firdevs Cansu Ogretmen, Besim Williams, Katelyn M. Davies, Christopher El Oualid, Farid Wasmuth, Elizabeth V. Olsen, Shaun K. |
author_facet | Yuan, Lingmin Gao, Fei Lv, Zongyang Nayak, Digant Nayak, Anindita Santos Bury, Priscila dos Cano, Kristin E. Jia, Lijia Oleinik, Natalia Atilgan, Firdevs Cansu Ogretmen, Besim Williams, Katelyn M. Davies, Christopher El Oualid, Farid Wasmuth, Elizabeth V. Olsen, Shaun K. |
author_sort | Yuan, Lingmin |
collection | PubMed |
description | The E1 enzyme Uba6 initiates signal transduction by activating ubiquitin and the ubiquitin-like protein FAT10 in a two-step process involving sequential catalysis of adenylation and thioester bond formation. To gain mechanistic insights into these processes, we determined the crystal structure of a human Uba6/ubiquitin complex. Two distinct architectures of the complex are observed: one in which Uba6 adopts an open conformation with the active site configured for catalysis of adenylation, and a second drastically different closed conformation in which the adenylation active site is disassembled and reconfigured for catalysis of thioester bond formation. Surprisingly, an inositol hexakisphosphate (InsP6) molecule binds to a previously unidentified allosteric site on Uba6. Our structural, biochemical, and biophysical data indicate that InsP6 allosterically inhibits Uba6 activity by altering interconversion of the open and closed conformations of Uba6 while also enhancing its stability. In addition to revealing the molecular mechanisms of catalysis by Uba6 and allosteric regulation of its activities, our structures provide a framework for developing Uba6-specific inhibitors and raise the possibility of allosteric regulation of other E1s by naturally occurring cellular metabolites. |
format | Online Article Text |
id | pubmed-9391358 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93913582022-08-21 Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6 Yuan, Lingmin Gao, Fei Lv, Zongyang Nayak, Digant Nayak, Anindita Santos Bury, Priscila dos Cano, Kristin E. Jia, Lijia Oleinik, Natalia Atilgan, Firdevs Cansu Ogretmen, Besim Williams, Katelyn M. Davies, Christopher El Oualid, Farid Wasmuth, Elizabeth V. Olsen, Shaun K. Nat Commun Article The E1 enzyme Uba6 initiates signal transduction by activating ubiquitin and the ubiquitin-like protein FAT10 in a two-step process involving sequential catalysis of adenylation and thioester bond formation. To gain mechanistic insights into these processes, we determined the crystal structure of a human Uba6/ubiquitin complex. Two distinct architectures of the complex are observed: one in which Uba6 adopts an open conformation with the active site configured for catalysis of adenylation, and a second drastically different closed conformation in which the adenylation active site is disassembled and reconfigured for catalysis of thioester bond formation. Surprisingly, an inositol hexakisphosphate (InsP6) molecule binds to a previously unidentified allosteric site on Uba6. Our structural, biochemical, and biophysical data indicate that InsP6 allosterically inhibits Uba6 activity by altering interconversion of the open and closed conformations of Uba6 while also enhancing its stability. In addition to revealing the molecular mechanisms of catalysis by Uba6 and allosteric regulation of its activities, our structures provide a framework for developing Uba6-specific inhibitors and raise the possibility of allosteric regulation of other E1s by naturally occurring cellular metabolites. Nature Publishing Group UK 2022-08-19 /pmc/articles/PMC9391358/ /pubmed/35986001 http://dx.doi.org/10.1038/s41467-022-32613-5 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 Yuan, Lingmin Gao, Fei Lv, Zongyang Nayak, Digant Nayak, Anindita Santos Bury, Priscila dos Cano, Kristin E. Jia, Lijia Oleinik, Natalia Atilgan, Firdevs Cansu Ogretmen, Besim Williams, Katelyn M. Davies, Christopher El Oualid, Farid Wasmuth, Elizabeth V. Olsen, Shaun K. Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6 |
title | Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6 |
title_full | Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6 |
title_fullStr | Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6 |
title_full_unstemmed | Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6 |
title_short | Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6 |
title_sort | crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/fat10 e1 enzyme uba6 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9391358/ https://www.ncbi.nlm.nih.gov/pubmed/35986001 http://dx.doi.org/10.1038/s41467-022-32613-5 |
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