Figure 2: Reaction Cycle for Hsp90. Hsp90 functions as a dimer in a cycle of client binding, ATP binding, ATPase activity, and nucleotide exchange as with Hsp70. The dimers are in an open conformation when empty and a more closed conformation when ATP binds. Substrate binding is assisted by co-chaperone Sgt1. For Hsp90, in which prolonged “holding” of clients seems an important component of its cellular function, the co-chaperones p23 and Cdc37 inhibit ATPase activity and stabilize Hsp90 client complexes. For nucleotide exchange to take place after ATPase activity eventually occurs, Aha1 functions as an exchange factor. As with Hsp70, triage of the protein between pathways of protein quality control involves scaffold protein Hop that binds the C-terminal TPR domain-binding motif (TBD). Through the TBP, Hsp90 can interact with a range of TPR domain containing co-chaperones that regulate intracellular function.