The proteasome is the central protease for intracellular protein breakdown. Coordinated binding and hydrolysis of ATP by the six proteasomal ATPase subunits induces conformational changes that drive the unfolding and translocation of substrates into the proteolytic 20S core particle for degradation. Here, we combine genetic and biochemical approaches with cryo-electron microscopy and integrative modeling to dissect the relationship between individual nucleotide binding events and proteasome conformational dynamics. We demonstrate unique impacts of ATP binding by individual ATPases on the proteasome conformational distribution and report two conformational states of the proteasome suggestive of a rotary ATP hydrolysis mechanism. These structures, coupled with functional analyses, reveal key roles for the ATPases Rpt1 and Rpt6 in gating substrate entry into the core particle. This deepened knowledge of proteasome conformational dynamics reveals key elements of intersubunit communication within the proteasome and clarifies the regulation of substrate entry into the proteolytic chamber.
Pubmed ID: 30067984 RIS Download
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View all literature mentionsThis monoclonal targets Ubiquitin
View all literature mentionsThis monoclonal targets HA.11
View all literature mentionsThis monoclonal targets V5 Tag
View all literature mentionsThis polyclonal targets Proteasome 20S core subunits
View all literature mentionsThis polyclonal targets Proteasome 19S Rpt5/S6a subunit pAb
View all literature mentionsThis polyclonal targets Proteasome 19S Rpt2/S4 (mts2) subunit pAb
View all literature mentionsThis unknown targets Glucose-6-Phosphate Dehydrogenase (G-6-PDH)
View all literature mentionsThis monoclonal targets Ubiquitin
View all literature mentionsThis monoclonal targets HA.11
View all literature mentionsThis unknown targets Glucose-6-Phosphate Dehydrogenase (G-6-PDH)
View all literature mentionsThis monoclonal targets Ubiquitin
View all literature mentionsThis monoclonal targets HA.11
View all literature mentionsThis monoclonal targets V5 Tag
View all literature mentionsThis polyclonal targets Proteasome 20S core subunits
View all literature mentionsThis polyclonal targets Proteasome 19S Rpt5/S6a subunit pAb
View all literature mentionsThis polyclonal targets Proteasome 19S Rpt2/S4 (mts2) subunit pAb
View all literature mentionsThis monoclonal targets HA.11
View all literature mentionsThis monoclonal targets V5 Tag
View all literature mentionsThis polyclonal targets Proteasome 20S core subunits
View all literature mentionsThis polyclonal targets Proteasome 19S Rpt5/S6a subunit pAb
View all literature mentionsThis polyclonal targets Proteasome 19S Rpt2/S4 (mts2) subunit pAb
View all literature mentions