Specific lid-base contacts in the 26S proteasome control the conformational switching required for substrate degradation
- University of California, Berkeley, United States
- The Scripps Research Institute, United States
- Celgene, United States
Abstract
The 26S proteasome is essential for proteostasis and the regulation of vital processes through ATP-dependent degradation of ubiquitinated substrates. To accomplish the multi-step degradation process, the proteasome's regulatory particle, consisting of lid and base subcomplexes, undergoes major conformational changes whose origin is unknown. Investigating the Saccharomyces cerevisiae proteasome, we found that peripheral interactions between the lid subunit Rpn5 and the base AAA+-ATPase ring are important for stabilizing the substrate-engagement-competent state and coordinating the conformational switch to processing states upon substrate engagement. Disrupting these interactions perturbs the conformational equilibrium and interferes with degradation initiation, while later processing steps remain unaffected. Similar defects in early degradation steps are observed when eliminating hydrolysis in the ATPase subunit Rpt6, whose nucleotide state seems to control proteasome conformational transitions. These results provide important insight into interaction networks that coordinate conformational changes with various stages of degradation, and how modulators of conformational equilibria may influence substrate turnover.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
Howard Hughes Medical Institute
- Andreas Martin
National Institutes of Health (R01-GM094497)
- Andreas Martin
National Institutes of Health (DP2EB020402)
- Gabriel C Lander
American Cancer Society (132279-PF-18-189-01-DMC)
- Andres H de la Peña
Pew Charitable Trusts
- Gabriel C Lander
National Institutes of Health (S10OD021634)
- Gabriel C Lander
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Greene et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Specific lid-base contacts in the 26S proteasome control the conformational switching required for substrate degradation
eLife 8:e49806.
https://doi.org/10.7554/eLife.49806
