8.A.249.  The 26 S Proteosome (26SP) Family 

Substrate-engaged 26 S proteasome structures have suggested the mechanisms for ATP-hydrolysis-driven protein translocation (de la Peña et al. 2018).  The 26 S proteasome is the primary eukaryotic degradation machine and thus is critically involved in numerous cellular processes. The heterohexameric adenosine triphosphatase (ATPase) motor of the proteasome unfolds and translocates targeted protein substrates into the open gate of a proteolytic core while a proteasomal deubiquitinase concomitantly removes substrate-attached ubiquitin chains. de la Peña et al. 2018 presented the cryo-EM structures of four distinct conformational states of the actively ATP-hydrolyzing, substrate-engaged 26 S proteasome. These structures reveal how mechanical substrate translocation accelerates deubiquitination and how ATP-binding, -hydrolysis, and phosphate-release events are coordinated within the AAA+ (ATPases associated with diverse cellular activities) motor to induce conformational changes and propel the substrate through the central pore (de la Peña et al. 2018).

The eukaryotic ubiquitin-proteasome system is responsible for most aspects of regulatory and quality-control protein degradation in cells (Tomko and Hochstrasser 2013). Its substrates, which are usually modified by polymers of ubiquitin, are ultimately degraded by the 26S proteasome. This 2.6-MDa protein complex is separated into a barrel-shaped proteolytic 20S core particle (CP) of 28 subunits capped on one or both ends by a 19S regulatory particle (RP) comprising at least 19 subunits. The RP coordinates substrate recognition, removal of substrate polyubiquitin chains, and substrate unfolding and translocation into the CP for degradation. Although many atomic structures of the CP have been determined, the RP has resisted high-resolution analysis. A combination of cryo-EM, biochemical analysis, and crystal structure determination of several RP subunits has yielded a near-atomic-resolution view of much of the complex. Major new insights into chaperone-assisted proteasome assembly have also recently emerged (Tomko and Hochstrasser 2013).