Structural basis of Hsp90 function

Heat shock protein 90 (Hsp90) stands at the crossroads of many signaling pathways responsible for cell proliferation, differentiation, cell homeostasis and apoptosis. Consequently, it is no surprise that Hsp90 is associated with all the six hallmarks of cancer and has become a prime anticancer target. Central to the Hsp90 mechanism is its ATPase activity, which is coupled to a conformational cycle involving a complex set of structural changes that involve all Hsp90 domains. The mechanism by which Hsp90 activates “client” protein is still poorly understood. However, there has been excellent progress on elucidating the molecular details of the complex structural changes required for Hsp90’s catalytically active state and how this activity is influenced by a variety of co-chaperones and client proteins. This review aims to bring together structural investigations that have so far contributed to our understanding of this ATPase-coupled conformational cycle and how this activity is regulated and ultimately has become the prime target for Hsp90 drugs