Formation of alternative proteasomes: Same lady, different cap?

► The Hb-Y-X motif is conserved in many eukaryotic Cdc48/p97 complexes. ► Both the p97 and CSN complexes show architectural paralogy to the 19S proteasome. ► The CSN complex binds p97 and could potentially form a 19S-like cap. ► We hypothesize that p97/CSN forms a promiscuous proteasome activator. The 26S proteasome is thought to be a homogenous complex, consisting of a 20S proteolytic core and a 19S regulatory particle that is required for its activation. Two groups have recently reported the activation of archeal 20S by a p97-related double-ring AAA+ ATPase complex, in a similar fashion to that reported for 19S. Since p97 is found in eukaryotes, the existence of a parallel setting in higher organisms is intriguing. Herein, we present supporting data and hypothesize that in eukaryotes, p97 and CSN form a promiscuous, hence hard-to-detect, “alternative cap”, enabling the prompt and precise elimination of particular substrates.