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Expanded Coverage of the 26S Proteasome Conformational Landscape Reveals Mechanisms of Peptidase Gating
Author(s) -
Tomko Robert J.,
Reed Randi G.,
Eisele Markus R.,
Rudack Till,
Schweitzer Andreas,
Beck Florian,
Nagy Istvan,
Pfeifer Guenter,
Plitzko Juergen M.,
Baumeister Wolfgang,
Sakata Eri
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.466.5
Subject(s) - proteasome , aaa proteins , gating , atp hydrolysis , atpase , biophysics , microbiology and biotechnology , intracellular , chemistry , protease , biochemistry , structural biology , proteolysis , ubiquitin , protein degradation , biology , enzyme , gene
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 as‐yet unidentified 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. Support or Funding Information NIH 1R01GM118600 (RJT) German Science Foundation (Excellence Cluster CIPSM and SFB‐1035/ Project A01) Marie Curie Career Integration Grant (PCIG14‐GA‐2013‐631577) (ES) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .