Gates, Channels, and Switches: Elements of the Proteasome Machine

The proteasome has emerged as an intricate machine that has dynamic mechanisms to regulate the timing of its activity, its selection of substrates, and its processivity. The 19-subunit regulatory particle (RP) recognizes ubiquitinated proteins, removes ubiquitin, and injects the target protein into the proteolytic chamber of the core particle (CP) via a narrow channel. Translocation into the CP requires substrate unfolding, which is achieved through mechanical force applied by a hexameric ATPase ring of the RP. Recent cryoelectron microscopy (cryoEM) studies have defined distinct conformational states of the RP, providing illustrative snapshots of what appear to be progressive steps of substrate engagement. Here, we bring together this new information with molecular analyses to describe the principles of proteasome activity and regulation.