Abstract
Hsp90 is a highly conserved ATP-dependent molecular chaperone that forms a clamp around client proteins. The role of ATP in Hsp90 function is unclear since cell viability requires ATP binding, but not hydrolysis. Here, we present findings that support our hypothesis that after ATP binds, the γ phosphate repositions in a regulated manner to interact with a conserved arginine (R380) and stabilize the closed clamp. We propose that the essential role of ATP in Hsp90 function is structural: ATP is a linker that physically tethers the N and M domains and stabilizes closing. Severing this link by hydrolysis facilitates reopening. Our findings support the idea that R380 is an arginine finger, a motif found in diverse NTPase families, due to its interdomain interaction with ATP. This in turn suggests that for some arginine fingers the nucleotide itself is a structural element important for stabilization of inter-domain or -subunit interactions.