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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| Format: | Article |
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MDPI AG
2020-12-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/12/1642 |
| _version_ | 1827700593687265280 |
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| author | Peter Tsvetkov Nadav Myers Julia Adler Yosef Shaul |
| author_facet | Peter Tsvetkov Nadav Myers Julia Adler Yosef Shaul |
| author_sort | Peter Tsvetkov |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T14:16:13Z |
| format | Article |
| id | doaj.art-166c193e25bd40aba98c98e4323dd528 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T14:16:13Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-166c193e25bd40aba98c98e4323dd5282023-11-20T23:43:17ZengMDPI AGBiomolecules2218-273X2020-12-011012164210.3390/biom10121642Degradation of Intrinsically Disordered Proteins by the NADH 26S ProteasomePeter Tsvetkov0Nadav Myers1Julia Adler2Yosef Shaul3Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, IsraelThe 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.https://www.mdpi.com/2218-273X/10/12/1642proteostasisubiquitin independent degradationintrinsically disordered proteinsNADH-26S proteasome |
| spellingShingle | Peter Tsvetkov Nadav Myers Julia Adler Yosef Shaul Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome Biomolecules proteostasis ubiquitin independent degradation intrinsically disordered proteins 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 | proteostasis ubiquitin independent degradation intrinsically disordered proteins NADH-26S proteasome |
| url | https://www.mdpi.com/2218-273X/10/12/1642 |
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