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

  • Source:
    eLife. 2016; 5.
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    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.| |The proteins contained within cells are constantly under scrutiny by a sophisticated “quality control” system that tags damaged or malfunctioning proteins with chains made up of a protein called ubiquitin. These ubiquitin chains serve as markers that target these toxic proteins for destruction by a molecular complex called the proteasome.|Removing ubiquitin chains from toxic proteins is a critical step in their degradation by the proteasome. This task is accomplished by an enzyme called a deubiquitinase, whose activity is tightly controlled. However, it was not clear how this enzyme is kept inactive before it is incorporated into the proteasome complex.|The deubiquitinase is part of a sub-complex called the “lid”, which attaches to the side of the proteasome. Dambacher, Worden, Herzik et al. used electron microscopy to solve the structure of the lid complex in high detail – so that it was almost possible to view individual atoms. This revealed that the deubiquitinase was in a conformation that was very different from what had previously been observed in fully assembled proteasomes.|The structures revealed that within the lid complex, a complicated network of interactions causes the deubiquitinase to be encompassed by neighboring subunits. This prevents the enzyme from interacting with ubiquitin chains. Importantly, this network of interactions appears to be set on a hair-trigger, as mutations that disrupt these interactions cause the deubiquitinase to be activated. As the lid complex integrates into the proteasome, the lid undergoes large-scale structural rearrangements; Dambacher, Worden, Herzik et al. expect that these disrupt the interactions that maintain the deubiquitinase in an inhibited conformation.|Due to their ability to regulate the activity of the proteasome, deubiquitinases are becoming increasingly popular drug targets. Therefore, probing how they are activated in more detail will be of great importance to cell biologists and also contribute substantially to biomedical research.|
  • Source:
    eLife. 2016; 5.
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