Marc Wehmer, Till Rudack, Florian Beck, Antje Aufderheide, Günter Pfeifer,
Jürgen M. Plitzko, Friedrich Förster, Klaus Schulten, Wolfgang
Baumeister, and Eri Sakata.
Structural insights into the functional cycle of the ATPase module
of the 26S proteasome.
Proceedings of the National Academy of Sciences, USA,
114:1305-1310, 2017.
(PMC: PMC5307450)
WEHM2017
In eukaryotic cells, the ubiquitin/proteasome system (UPS) is
responsible for the regulated degradation of intracellular proteins.
The 26S holocomplex comprises the core particle (CP), where proteolysis takes
place, and one or two regulatory particles (RPs). The
base of the RP is formed by a heterohexameric AAA+ ATPase
module, which unfolds and translocates substrates into the CP. Applying
single-particle cryo-electron microscopy (cryo-EM) and image classification to
samples in the presence of different nucleotides and nucleotide analogs, we
were able to observe four distinct conformational
states (s1 to s4). The resolution of the four conformers allowed for
the construction of atomic models of the AAA+ ATPase module
as it
progresses through the functional cycle. In a hitherto unobserved
state (s4), the gate controlling access to the CP is open. The structures
described in this study allow us to put forward a model for the 26S
functional cycle driven by ATP hydrolysis.
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