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Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family
Controlled degradation of proteins is necessary for ensuring their abundance and sustaining a healthy and accurately functioning proteome. One of the degradation routes involves the uncapped 20S proteasome, which cleaves proteins with a partially unfolded region, including those that are damaged or...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10229617/ https://www.ncbi.nlm.nih.gov/pubmed/37253751 http://dx.doi.org/10.1038/s41467-023-38404-w |
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author | Deshmukh, Fanindra Kumar Ben-Nissan, Gili Olshina, Maya A. Füzesi-Levi, Maria G. Polkinghorn, Caley Arkind, Galina Leushkin, Yegor Fainer, Irit Fleishman, Sarel J. Tawfik, Dan Sharon, Michal |
author_facet | Deshmukh, Fanindra Kumar Ben-Nissan, Gili Olshina, Maya A. Füzesi-Levi, Maria G. Polkinghorn, Caley Arkind, Galina Leushkin, Yegor Fainer, Irit Fleishman, Sarel J. Tawfik, Dan Sharon, Michal |
author_sort | Deshmukh, Fanindra Kumar |
collection | PubMed |
description | Controlled degradation of proteins is necessary for ensuring their abundance and sustaining a healthy and accurately functioning proteome. One of the degradation routes involves the uncapped 20S proteasome, which cleaves proteins with a partially unfolded region, including those that are damaged or contain intrinsically disordered regions. This degradation route is tightly controlled by a recently discovered family of proteins named Catalytic Core Regulators (CCRs). Here, we show that CCRs function through an allosteric mechanism, coupling the physical binding of the PSMB4 β-subunit with attenuation of the complex’s three proteolytic activities. In addition, by dissecting the structural properties that are required for CCR-like function, we could recapitulate this activity using a designed protein that is half the size of natural CCRs. These data uncover an allosteric path that does not involve the proteasome’s enzymatic subunits but rather propagates through the non-catalytic subunit PSMB4. This way of 20S proteasome-specific attenuation opens avenues for decoupling the 20S and 26S proteasome degradation pathways as well as for developing selective 20S proteasome inhibitors. |
format | Online Article Text |
id | pubmed-10229617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-102296172023-06-01 Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family Deshmukh, Fanindra Kumar Ben-Nissan, Gili Olshina, Maya A. Füzesi-Levi, Maria G. Polkinghorn, Caley Arkind, Galina Leushkin, Yegor Fainer, Irit Fleishman, Sarel J. Tawfik, Dan Sharon, Michal Nat Commun Article Controlled degradation of proteins is necessary for ensuring their abundance and sustaining a healthy and accurately functioning proteome. One of the degradation routes involves the uncapped 20S proteasome, which cleaves proteins with a partially unfolded region, including those that are damaged or contain intrinsically disordered regions. This degradation route is tightly controlled by a recently discovered family of proteins named Catalytic Core Regulators (CCRs). Here, we show that CCRs function through an allosteric mechanism, coupling the physical binding of the PSMB4 β-subunit with attenuation of the complex’s three proteolytic activities. In addition, by dissecting the structural properties that are required for CCR-like function, we could recapitulate this activity using a designed protein that is half the size of natural CCRs. These data uncover an allosteric path that does not involve the proteasome’s enzymatic subunits but rather propagates through the non-catalytic subunit PSMB4. This way of 20S proteasome-specific attenuation opens avenues for decoupling the 20S and 26S proteasome degradation pathways as well as for developing selective 20S proteasome inhibitors. Nature Publishing Group UK 2023-05-30 /pmc/articles/PMC10229617/ /pubmed/37253751 http://dx.doi.org/10.1038/s41467-023-38404-w Text en © The Author(s) 2023 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 Deshmukh, Fanindra Kumar Ben-Nissan, Gili Olshina, Maya A. Füzesi-Levi, Maria G. Polkinghorn, Caley Arkind, Galina Leushkin, Yegor Fainer, Irit Fleishman, Sarel J. Tawfik, Dan Sharon, Michal Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family |
title | Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family |
title_full | Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family |
title_fullStr | Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family |
title_full_unstemmed | Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family |
title_short | Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family |
title_sort | allosteric regulation of the 20s proteasome by the catalytic core regulators (ccrs) family |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10229617/ https://www.ncbi.nlm.nih.gov/pubmed/37253751 http://dx.doi.org/10.1038/s41467-023-38404-w |
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