Specific lid-base contacts in the 26S proteasome control the conformational switching required for substrate engagement and degradation
| Autor: | Andrew D. Martin, Eric R. Greene, Ellen A. Goodall, Andres H. de la Peña, Mary E Matyskiela, Gabriel C. Lander |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences biology Chemistry Protein subunit ATPase Saccharomyces cerevisiae Substrate (chemistry) Protein degradation biology.organism_classification 03 medical and health sciences 0302 clinical medicine Ubiquitin Proteasome biology.protein Biophysics Nucleotide 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/687921 |
| Popis: | The 26S proteasome is essential for protein homeostasis and the regulation of vital cellular processes through ATP-dependent degradation of ubiquitinated substrates. To accomplish the multi-step reaction of protein degradation, the proteasome’s regulatory particle, consisting of the lid and base subcomplexes, undergoes major conformational changes whose origin and control are largely unknown. Investigating the Saccharomyces cerevisiae 26S proteasome, we found that peripheral interactions between the lid subunit Rpn5 and the base AAA+ ATPase ring play critical roles in stabilizing the substrate-engagement-competent state and coordinating the conformational switch to processing states after a substrate has been engaged. Disrupting these interactions perturbs the conformational equilibrium and interferes with degradation initiation, while later steps of substrate processing remain unaffected. Similar defects in the early degradation steps are also observed when eliminating hydrolysis in the ATPase subunit Rpt6, whose nucleotide state seems to control conformational transitions of the proteasome. These results provide important insight into the network of interactions that coordinate conformational changes with various stages of proteasomal degradation, and how modulators of conformational equilibria may influence substrate turnover. |
| Databáze: | OpenAIRE |
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