“Tuning” the ATPase activity of Hsp90

The Hsp90 chaperone is responsible for the activation and maturation of an eclectic set of proteins. These are often key regulatory proteins that include protein kinases, steroid hormone receptors and transcription factors. Consequently, Hsp90 has become one of the most important anti-cancer targets of our time, as well as a target for other diseases, such a neurodegenerative, parasitic and viral diseases. The ATPase activity of Hsp90 is central to its mechanistic action and the binding and hydrolysis of ATP drives a conformational cycle that brings about activation and maturation of client proteins. The structurally diverse clientele of Hsp90 necessitates that Hsp90 co-operates with a variety of co-chaperones that modulate and tune its activity and thus its conformational cycle. Delivering client proteins is one role that specific co-chaperones play, while others stabilize client complex or provide directionality and alterations to the ATP-coupled conformational cycle of Hsp90. The formation of a catalytically active unit, able to hydrolyze ATP, involves all regions of Hsp90. This complexity has facilitated the evolution of a variety of co-chaperones that regulate Hsp90 by modulating different molecular switches within the chaperone. It has also allowed the evolution of Hsp90 orthologues that are kinetically different. Furthermore, it appears that the conformational switches of Hsp90 are not always coupled. Here, we describe the known Hsp90-co-chaperone complexes, the role that specific co-chaperones play in these complexes and, briefly, post-translational modifications that affect the ATPase activity of Hsp90.