Magical moments in protease biology: proteasome autocatalytic activation and PI31-mediated inhibition

Proteases regulate nearly every aspect of cellular function. Spatial and temporal control of protease activity contributes to this functional versatility and includes both zymogen activation mechanisms and the existence of dedicated protease inhibitors. Unlike conventional proteases, the proteasome harbors six individual proteases within a single macromolecular complex. This unique arrangement poses formidable challenges by requiring simultaneous activation or inhibition of all six active sites. Recent work from multiple labs has uncovered key aspects of assembly-coupled autocatalytic activation as well as the mechanism of proteasome inhibition by the endogenous inhibitor PI31 (proteasome inhibitor 31 kDa). These elegant mechanisms highlight and expand the remarkable complexity and beauty of protease biology.