Figure 1: Reaction cycle for Hsp70 family polypeptides. Hsp70 proteins are portrayed as consisting of two major functional domains, including an N-terminal ATPase domain and a C-terminal client protein binding domain. When ATP occupies the ATPase domain, the C-terminal client protein-binding domain has weak affinity for clients. In the first step in chaperoning, the client protein (here depicted as unfolded) associated with a J domain protein (JDP) is able to bind Hsp70. This interaction causes allosteric changes in the N-terminal ATPase domain, ATP hydrolysis, and tight binding of substrate. Release of the client is then associated with nucleotide exchange loss of ADP and phosphate and replacement with ATP. In order to occur at a significant rate in cells nucleotide exchange factors such as Bag1 and HspBP1 are required. Released client is depicted as “folded.” However, the precise nature of the processes involved in achieving this state are not clear. We also show an alternative fate for Hsp70 client complexes involving the scaffold protein Hop. Hop can bind the extreme C-terminus of Hsp70 and couple it to other proteins such as Hsp90. Clients can thus be passed from Hsp70 to Hsp90 in a coordinated folding process.