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Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation
Protein degradation, a major eukaryotic response to cellular signals, is subject to numerous layers of regulation. In yeast, the evolutionarily conserved GID E3 ligase mediates glucose-induced degradation of fructose-1,6-bisphosphatase (Fbp1), malate dehydrogenase (Mdh2), and other gluconeogenic enz...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160049/ https://www.ncbi.nlm.nih.gov/pubmed/35650207 http://dx.doi.org/10.1038/s41467-022-30803-9 |
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author | Qiao, Shuai Lee, Chia-Wei Sherpa, Dawafuti Chrustowicz, Jakub Cheng, Jingdong Duennebacke, Maximilian Steigenberger, Barbara Karayel, Ozge Vu, Duc Tung von Gronau, Susanne Mann, Matthias Wilfling, Florian Schulman, Brenda A. |
author_facet | Qiao, Shuai Lee, Chia-Wei Sherpa, Dawafuti Chrustowicz, Jakub Cheng, Jingdong Duennebacke, Maximilian Steigenberger, Barbara Karayel, Ozge Vu, Duc Tung von Gronau, Susanne Mann, Matthias Wilfling, Florian Schulman, Brenda A. |
author_sort | Qiao, Shuai |
collection | PubMed |
description | Protein degradation, a major eukaryotic response to cellular signals, is subject to numerous layers of regulation. In yeast, the evolutionarily conserved GID E3 ligase mediates glucose-induced degradation of fructose-1,6-bisphosphatase (Fbp1), malate dehydrogenase (Mdh2), and other gluconeogenic enzymes. “GID” is a collection of E3 ligase complexes; a core scaffold, RING-type catalytic core, and a supramolecular assembly module together with interchangeable substrate receptors select targets for ubiquitylation. However, knowledge of additional cellular factors directly regulating GID-type E3s remains rudimentary. Here, we structurally and biochemically characterize Gid12 as a modulator of the GID E3 ligase complex. Our collection of cryo-EM reconstructions shows that Gid12 forms an extensive interface sealing the substrate receptor Gid4 onto the scaffold, and remodeling the degron binding site. Gid12 also sterically blocks a recruited Fbp1 or Mdh2 from the ubiquitylation active sites. Our analysis of the role of Gid12 establishes principles that may more generally underlie E3 ligase regulation. |
format | Online Article Text |
id | pubmed-9160049 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91600492022-06-03 Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation Qiao, Shuai Lee, Chia-Wei Sherpa, Dawafuti Chrustowicz, Jakub Cheng, Jingdong Duennebacke, Maximilian Steigenberger, Barbara Karayel, Ozge Vu, Duc Tung von Gronau, Susanne Mann, Matthias Wilfling, Florian Schulman, Brenda A. Nat Commun Article Protein degradation, a major eukaryotic response to cellular signals, is subject to numerous layers of regulation. In yeast, the evolutionarily conserved GID E3 ligase mediates glucose-induced degradation of fructose-1,6-bisphosphatase (Fbp1), malate dehydrogenase (Mdh2), and other gluconeogenic enzymes. “GID” is a collection of E3 ligase complexes; a core scaffold, RING-type catalytic core, and a supramolecular assembly module together with interchangeable substrate receptors select targets for ubiquitylation. However, knowledge of additional cellular factors directly regulating GID-type E3s remains rudimentary. Here, we structurally and biochemically characterize Gid12 as a modulator of the GID E3 ligase complex. Our collection of cryo-EM reconstructions shows that Gid12 forms an extensive interface sealing the substrate receptor Gid4 onto the scaffold, and remodeling the degron binding site. Gid12 also sterically blocks a recruited Fbp1 or Mdh2 from the ubiquitylation active sites. Our analysis of the role of Gid12 establishes principles that may more generally underlie E3 ligase regulation. Nature Publishing Group UK 2022-06-01 /pmc/articles/PMC9160049/ /pubmed/35650207 http://dx.doi.org/10.1038/s41467-022-30803-9 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 Qiao, Shuai Lee, Chia-Wei Sherpa, Dawafuti Chrustowicz, Jakub Cheng, Jingdong Duennebacke, Maximilian Steigenberger, Barbara Karayel, Ozge Vu, Duc Tung von Gronau, Susanne Mann, Matthias Wilfling, Florian Schulman, Brenda A. Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation |
title | Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation |
title_full | Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation |
title_fullStr | Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation |
title_full_unstemmed | Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation |
title_short | Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation |
title_sort | cryo-em structures of gid12-bound gid e3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160049/ https://www.ncbi.nlm.nih.gov/pubmed/35650207 http://dx.doi.org/10.1038/s41467-022-30803-9 |
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