Ubiquitin and some of its homologues target proteins to the proteasome for degradation. Other ubiquitin‐like domains are involved in cellular processes unrelated to the proteasome, and proteins containing these domains remain stable in the cell. We find that the 10 yeast ubiquitin‐like domains tested bind to the proteasome, and that all 11 identified domains can target proteins for degradation. Their apparent proteasome affinities are not directly related to their stabilities or functions. That is, ubiquitin‐like domains in proteins not part of the ubiquitin proteasome system may bind the proteasome more tightly than domains in proteins that are bona fide components. We propose that proteins with ubiquitin‐like domains have properties other than proteasome binding that confer stability. We show that one of these properties is the absence of accessible disordered regions that allow the proteasome to initiate degradation. In support of this model, we find that Mdy2 is degraded in yeast when a disordered region in the protein becomes exposed and that the attachment of a disordered region to Ubp6 leads to its degradation.
The lack of proteolysis‐initiating sequences stabilizes yeast ubiquitin‐like domain‐containing proteins despite their targeting to the proteasome, showing that protein stability is not solely controlled by proteasome affinity as determined by the UbL domains but also by the presence or absence of sites at which the proteasome can engage substrates to initiate the degradation.
10 out of 11 ubiquitin‐like (UbL) domains tested can bind to proteasome and target model proteins to degradation in vitro and in yeast.
Protein stability does not correlate directly with proteasome affinity but is modulated by accessibility of disordered region at which proteasomes can initiate the degradation.
Burying of a disordered region in the UbL domain protein Mdy2 by its binding partner Get4 protects Mdy2 from proteasomal degradation.
UbL domain protein Ubp6 is a stable proteasome‐associated subunit but becomes degraded when a disordered region is provided.
The EMBO Journal (2016) 35: 1522–1536
- Received September 26, 2015.
- Revision received April 26, 2016.
- Accepted April 27, 2016.
- © 2016 The Authors
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