Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition

The 26S proteasome is responsible for the selective, ATP-dependent degradation of polyubiquitinated cellular proteins. Removal of ubiquitin chains from targeted substrates at the proteasome is a prerequisite for substrate processing and is accomplished by Rpn11, a deubiquitinase within the 'lid...

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Bibliographic Details
Published in:	eLife 2016-01, Vol.5, p.e13027
Main Authors:	Dambacher, Corey M, Worden, Evan J, Herzik, Mark A, Martin, Andreas, Lander, Gabriel C
Format:	Article
Language:	eng
Subjects:	Biophysics and Structural Biology Cryoelectron Microscopy cryoEM Deubiquitinating Enzymes - antagonists & inhibitors deubiquitination DNA Mutational Analysis Electron microscopy Enzymes Fourier transforms Microscopy Models, Molecular Mutagenesis proteasome Proteasome 26S Proteasome Endopeptidase Complex - chemistry Proteasome Endopeptidase Complex - metabolism Proteasome Endopeptidase Complex - ultrastructure Proteins Saccharomyces cerevisiae Saccharomyces cerevisiae - chemistry Saccharomyces cerevisiae - enzymology Ubiquitin
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Summary:	The 26S proteasome is responsible for the selective, ATP-dependent degradation of polyubiquitinated cellular proteins. Removal of ubiquitin chains from targeted substrates at the proteasome is a prerequisite for substrate processing and is accomplished by Rpn11, a deubiquitinase within the 'lid' sub-complex. Prior to the lid's incorporation into the proteasome, Rpn11 deubiquitinase activity is inhibited to prevent unwarranted deubiquitination of polyubiquitinated proteins. Here we present the atomic model of the isolated lid sub-complex, as determined by cryo-electron microscopy at 3.5 Å resolution, revealing how Rpn11 is inhibited through its interaction with a neighboring lid subunit, Rpn5. Through mutagenesis of specific residues, we describe the network of interactions that are required to stabilize this inhibited state. These results provide significant insight into the intricate mechanisms of proteasome assembly, outlining the substantial conformational rearrangements that occur during incorporation of the lid into the 26S holoenzyme, which ultimately activates the deubiquitinase for substrate degradation.
ISSN:	2050-084X 2050-084X