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Free keywords:
Assembly chaperones; Chaperones; Cryo-electron microscopy; De-ubiquitylating enzymes; ER-associated degradation (ERAD); Misfolded proteins; Mitochondria-associated degradation; Protein degradation; Protein-protein interactions; 26S proteasome; Ubiquitin; Ubiquitin ligases; Ubiquitin-proteasome pathway; Ubiquitin receptors
Abstract:
The 26S proteasome is a molecular machine of approximately 2.5 MDa, which degrades ubiquitylated proteins in an ATP-dependent manner. It comprises two modules, the 20S proteasome and one or two copies of asymmetric 19S regulatory particles (RPs), which bind to the end(s) of the barrel-shaped 20S proteasome. Proteolytic action occurs at the heart of the 20S proteasome, whereas the 19S RP is responsible for regulation of 20S proteasome, which involves substrate recognition, substrate deubiquitylation, opening of the gate to the inner cavity of the 20S proteasome, substrate unfolding, and translocation to the 20S proteasome.
In this article, we describe the structure, mechanism, and function of the 26S proteasome based on recent studies. Cryoelectron microscopy maps of the 26S proteasome and protein–protein interaction data start to unveil the molecular architecture of the 26S proteasome. Moreover, the complex assembly pathway of the 26S proteasome has been elucidated to considerable extent. An increasingly complex picture of proteasomal regulation in the cell emerges: interactions with chaperones tightly couples chaperone-mediated folding and degradation, interactions with E3 ubiquitin ligases correlate ubiquitylation and degradation, and AAA–ATPases escort substrates from organelles to the 26S proteasome.
