VCP/p97-Mediated Unfolding as a Principle in Protein Homeostasis and Signaling

The AAA+-type ATPase p97 governs an ever-expanding number of cellular processes reaching from degradation of damaged proteins and organelles to key signaling events and chromatin regulation with thousands of client proteins. With its relevance for cellular homeostasis and genome stability, it is linked to muscular and neuronal degeneration and, conversely, constitutes an attractive anti-cancer drug target. Its molecular function is ATP-driven protein unfolding, which is directed by ubiquitin and assisted by a host of cofactor proteins. This activity underlies p97' s diverse ability to pull proteins out of membranes, unfold proteins for proteasomal degradation, or segregate proteins from partners for downstream activity. Recent advances in structural analysis and biochemical reconstitution have underscored this notion, resolved detailed molecular motions within the p97 hexamer, and suggested substrate threading through the central channel of the p97 hexamer as the driving mechanism. We will discuss the mechanisms and open questions in the context of the diverse cellular activities.