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Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome

The 26S proteasome is the endpoint of the ubiquitin- and ATP-dependent degradation pathway. Over the years, ATP was regarded as completely essential for 26S proteasome function due to its role in ubiquitin-signaling, substrate unfolding and ensuring its structural integrity. We have previously repor...

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Autores principales: Tsvetkov, Peter, Myers, Nadav, Adler, Julia, Shaul, Yosef
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762313/
https://www.ncbi.nlm.nih.gov/pubmed/33297334
http://dx.doi.org/10.3390/biom10121642
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author Tsvetkov, Peter
Myers, Nadav
Adler, Julia
Shaul, Yosef
author_facet Tsvetkov, Peter
Myers, Nadav
Adler, Julia
Shaul, Yosef
author_sort Tsvetkov, Peter
collection PubMed
description The 26S proteasome is the endpoint of the ubiquitin- and ATP-dependent degradation pathway. Over the years, ATP was regarded as completely essential for 26S proteasome function due to its role in ubiquitin-signaling, substrate unfolding and ensuring its structural integrity. We have previously reported that physiological concentrations of NADH are efficient in replacing ATP to maintain the integrity of an enzymatically functional 26S PC. However, the substrate specificity of the NADH-stabilized 26S proteasome complex (26S PC) was never assessed. Here, we show that the binding of NADH to the 26S PC inhibits the ATP-dependent and ubiquitin-independent degradation of the structured ODC enzyme. Moreover, the NADH-stabilized 26S PC is efficient in degrading intrinsically disordered protein (IDP) substrates that might not require ATP-dependent unfolding, such as p27, Tau, c-Fos and more. In some cases, NADH-26S proteasomes were more efficient in processing IDPs than the ATP-26S PC. These results indicate that in vitro, physiological concentrations of NADH can alter the processivity of ATP-dependent 26S PC substrates such as ODC and, more importantly, the NADH-stabilized 26S PCs promote the efficient degradation of many IDPs. Thus, ATP-independent, NADH-dependent 26S proteasome activity exemplifies a new principle of how mitochondria might directly regulate 26S proteasome substrate specificity.
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spelling pubmed-77623132020-12-26 Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome Tsvetkov, Peter Myers, Nadav Adler, Julia Shaul, Yosef Biomolecules Article The 26S proteasome is the endpoint of the ubiquitin- and ATP-dependent degradation pathway. Over the years, ATP was regarded as completely essential for 26S proteasome function due to its role in ubiquitin-signaling, substrate unfolding and ensuring its structural integrity. We have previously reported that physiological concentrations of NADH are efficient in replacing ATP to maintain the integrity of an enzymatically functional 26S PC. However, the substrate specificity of the NADH-stabilized 26S proteasome complex (26S PC) was never assessed. Here, we show that the binding of NADH to the 26S PC inhibits the ATP-dependent and ubiquitin-independent degradation of the structured ODC enzyme. Moreover, the NADH-stabilized 26S PC is efficient in degrading intrinsically disordered protein (IDP) substrates that might not require ATP-dependent unfolding, such as p27, Tau, c-Fos and more. In some cases, NADH-26S proteasomes were more efficient in processing IDPs than the ATP-26S PC. These results indicate that in vitro, physiological concentrations of NADH can alter the processivity of ATP-dependent 26S PC substrates such as ODC and, more importantly, the NADH-stabilized 26S PCs promote the efficient degradation of many IDPs. Thus, ATP-independent, NADH-dependent 26S proteasome activity exemplifies a new principle of how mitochondria might directly regulate 26S proteasome substrate specificity. MDPI 2020-12-07 /pmc/articles/PMC7762313/ /pubmed/33297334 http://dx.doi.org/10.3390/biom10121642 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tsvetkov, Peter
Myers, Nadav
Adler, Julia
Shaul, Yosef
Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome
title Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome
title_full Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome
title_fullStr Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome
title_full_unstemmed Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome
title_short Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome
title_sort degradation of intrinsically disordered proteins by the nadh 26s proteasome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762313/
https://www.ncbi.nlm.nih.gov/pubmed/33297334
http://dx.doi.org/10.3390/biom10121642
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