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Most regulated proteolysis in cells is conducted by the ubiquitin-proteasome system (UPS), in which proteins to be eliminated are selected through multiple steps to achieve high specificity. The large protease complex proteasome binds to ubiquitin molecules that are attached to the substrate and further interacts with a disordered region in the target to initiate unfolding for degradation. Recent studies have expanded our view of the complexity of ubiquitination as well as the details of substrate engagement by the proteasome and at the same time have suggested the characteristics of substrates that are susceptible to proteasomal degradation. Here, I review some destabilizing elements of proteasome substrates with particular attention to ubiquitination, initiation region and stability against unfolding and discuss their interplay to determine the substrate stability. A spatial perspective is important to understand the mechanism of action of proteasomal degradation, which may be critical for drug development targeting the UPS including targeted protein degradation.

Structural and biochemical elements of efficiently degradable proteasome substrates