The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome
Summary: The 26S proteasome is the major compartmental protease in eukaryotic cells, responsible for the ATP-dependent turnover of obsolete, damaged, or misfolded proteins that are delivered for degradation through attached ubiquitin modifications. Besides targeting substrates to the proteasome, ubi...
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Elsevier
2025-06-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725005078 |
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| author | Zaw Min Htet Ken C. Dong Andreas Martin |
| author_facet | Zaw Min Htet Ken C. Dong Andreas Martin |
| author_sort | Zaw Min Htet |
| collection | DOAJ |
| description | Summary: The 26S proteasome is the major compartmental protease in eukaryotic cells, responsible for the ATP-dependent turnover of obsolete, damaged, or misfolded proteins that are delivered for degradation through attached ubiquitin modifications. Besides targeting substrates to the proteasome, ubiquitin was recently shown to promote degradation initiation by modulating proteasome conformational switching, yet the underlying mechanisms are unknown. Here, we use biochemical, mutational, and single-molecule fluorescence resonance energy transfer (FRET)-based approaches to show that the proteasomal deubiquitinase Rpn11 functions as an allosteric sensor and facilitates the early steps of degradation. After substrate recruitment to the proteasome, ubiquitin binding to Rpn11 interferes with conformation-specific interactions of the ubiquitin receptor subunit Rpn10, thereby stabilizing the proteasome’s engagement-competent state and expediting substrate insertion into the ATPase motor for mechanical translocation, unfolding, and Rpn11-mediated deubiquitination. These findings explain how modifications with poly-ubiquitin chains or multiple mono-ubiquitins allosterically promote substrate degradation and allow up to 4-fold faster turnover by the proteasome. |
| format | Article |
| id | doaj-art-373885a2dd1348b290dfadf72c28569b |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-373885a2dd1348b290dfadf72c28569b2025-08-20T01:52:55ZengElsevierCell Reports2211-12472025-06-0144611573610.1016/j.celrep.2025.115736The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasomeZaw Min Htet0Ken C. Dong1Andreas Martin2Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA 94720, USAHoward Hughes Medical Institute, University of California at Berkeley, Berkeley, CA 94720, USADepartment of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA 94720, USA; Corresponding authorSummary: The 26S proteasome is the major compartmental protease in eukaryotic cells, responsible for the ATP-dependent turnover of obsolete, damaged, or misfolded proteins that are delivered for degradation through attached ubiquitin modifications. Besides targeting substrates to the proteasome, ubiquitin was recently shown to promote degradation initiation by modulating proteasome conformational switching, yet the underlying mechanisms are unknown. Here, we use biochemical, mutational, and single-molecule fluorescence resonance energy transfer (FRET)-based approaches to show that the proteasomal deubiquitinase Rpn11 functions as an allosteric sensor and facilitates the early steps of degradation. After substrate recruitment to the proteasome, ubiquitin binding to Rpn11 interferes with conformation-specific interactions of the ubiquitin receptor subunit Rpn10, thereby stabilizing the proteasome’s engagement-competent state and expediting substrate insertion into the ATPase motor for mechanical translocation, unfolding, and Rpn11-mediated deubiquitination. These findings explain how modifications with poly-ubiquitin chains or multiple mono-ubiquitins allosterically promote substrate degradation and allow up to 4-fold faster turnover by the proteasome.http://www.sciencedirect.com/science/article/pii/S2211124725005078CP: Molecular biology |
| spellingShingle | Zaw Min Htet Ken C. Dong Andreas Martin The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome Cell Reports CP: Molecular biology |
| title | The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome |
| title_full | The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome |
| title_fullStr | The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome |
| title_full_unstemmed | The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome |
| title_short | The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome |
| title_sort | deubiquitinase rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26s proteasome |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725005078 |
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