Evolution of the role of Cdc48 and its interactions with the 20S peptidase (478.1)

Abstract

Proteasomes are ubiquitous ATP‐dependent proteases that function in eukarya, archaea, and actinobacteria. These proteolytic machines employ a barrel‐shaped 20S core peptidase and a hexameric AAA+ unfolding ring that unfolds and spools substrates into the chamber of the peptidase. Interestingly, the 20S peptidase can function with two very different types of AAA+ unfolding rings. For example, archaeal 20S can combine either with the double‐ring Cdc48 unfoldase or the single‐ring PAN unfoldase to execute ATP‐dependent proteolysis. Single‐ring AAA+ unfoldases that are homologous to PAN also function with the 20S in protein degradation in eukarya (the Rpt1‐6 ring of the 26S proteasome) and actinobacteria (Mpa). We will discuss differences between single‐ring and double‐ring AAA+ unfoldases, how the interactions between the 20S peptidase and its AAA+ partner are controlled, and possible mechanisms by which the N domain of Cdc48 controls rates of ATP hydrolysis, substrate unfolding, and affinity for the 20S peptidase.