Structural disorder and its role in proteasomal degradation

Abstract

The ubiquitin proteasome system is responsible for the controlled degradation of a vast number of intracellular proteins. It targets misfolded or otherwise aberrant proteins as well as proteins no longer needed at a given point in time. The 26S proteasome is a large macromolecular machine comprising 33 distinct subunits as well as a number of transiently associating cofactors. Being essentially a non-specific protease, specificity is conferred by the ubiquitin system, which selects and marks substrates for degradation. Here, we review our current understanding of the structure and function of the 26S proteasome; in doing so we highlight the role of disordered protein regions. Disordered segments in substrates promote their degradation, whereas low complexity regions prevent their proteolysis. In the 26S proteasome itself a main role of disordered segments seems to be rendering the ubiquitin receptors mobile, possibly supporting recruitment of polyubiquitylated substrates. Thus, these structural features of substrates as well as of the 26S proteasome itself likely play important roles at different stages of the protein degradation process.

Keywords: 26S proteasome; Disordered protein segment; Low complexity region; Protein degradation; Proteostasis; Structural variability.