Reprograming of the ubiquitin ligase Ubr1 by intrinsically disordered Roq1 through cooperating multifunctional motifs
One way cells control the speed and specificity of protein degradation is by regulating the activity of ubiquitin ligases. Upon proteotoxic stress in yeast, the intrinsically disordered protein Roq1 binds the ubiquitin ligase Ubr1 as a pseudosubstrate, thereby modulating the degradation of substrate...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 17, 2025
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| In: |
The EMBO journal
Year: 2025, Volume: 44, Issue: 6, Pages: 1774-1803 |
| ISSN: | 1460-2075 |
| DOI: | 10.1038/s44318-025-00375-7 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s44318-025-00375-7 Verlag, kostenfrei, Volltext: https://www.embopress.org/doi/full/10.1038/s44318-025-00375-7 
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| Author Notes: | Niklas Peters, Sibylle Kanngießer, Oliver Pajonk, Rafael Salazar Claros, Petra Hubbe, Axel Mogk & Sebastian Schuck |
MARC
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| 245 | 1 | 0 | |a Reprograming of the ubiquitin ligase Ubr1 by intrinsically disordered Roq1 through cooperating multifunctional motifs |c Niklas Peters, Sibylle Kanngießer, Oliver Pajonk, Rafael Salazar Claros, Petra Hubbe, Axel Mogk & Sebastian Schuck |
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| 520 | |a One way cells control the speed and specificity of protein degradation is by regulating the activity of ubiquitin ligases. Upon proteotoxic stress in yeast, the intrinsically disordered protein Roq1 binds the ubiquitin ligase Ubr1 as a pseudosubstrate, thereby modulating the degradation of substrates of the N-degron pathway and promoting the elimination of misfolded proteins. The mechanism underlying this reprograming of Ubr1 is unknown. Here, we show that Roq1 controls Ubr1 by means of two cooperating multifunctional motifs. The N-terminal arginine and a short hydrophobic motif of Roq1 interact with Ubr1 as part of a heterobivalent binding mechanism. Via its N-terminal arginine, Roq1 regulates the ubiquitination of various N-degron substrates and folded proteins. Via its hydrophobic motif, Roq1 accelerates the ubiquitination of misfolded proteins. These findings reveal how a small, intrinsically disordered protein with a simple architecture engages parallel channels of communication to reprogram a functionally complex ubiquitin ligase. | ||
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