Structure and Function of Hsp70 Molecular Chaperones

Hsp70s comprise a group of highly conserved chaperones essential to cellular homeostasis. They take part in a wide array of processes, including their key roles in protein homeostasis in which they guard the proteome by binding partially folded proteins, thus protecting them from aggregation and allowing them to fold. Hsp70s work through binding and release of hydrophobic protein segments at the C-terminal substrate-binding domain (SBD), the affinity of which is modulated by ATP binding and hydrolysis to the N-terminal nucleotide-binding domain (NBD): When ATP binds to the NBD, the SBD has low affinity for substrate; when ATP is hydrolyzed and ADP is bound to the NBD, the SBD has high substrate affinity. This allosteric mechanism is regulated by co-chaperones: J proteins deliver substrates to Hsp70s and accelerate ATP hydrolysis; nucleotide exchange factors facilitate exchange of ADP by ATP. In humans, Hsp70 members are expressed in all cell types and many subcellular compartments. The functional diversity of Hsp70s is stunning, including shepherding of nascent chains, protein translocation across membranes, disassembly of complexes and recovery of proteins from aggregates. Some Hsp70s focus on housekeeping functions, while others are highly expressed under stress, promote cell survival and are essential for the cell to cope with adverse conditions. Consequently, Hsp70s are crucial for tumor cells to thrive and constitute a promising target for cancer treatments; in addition, Hsp70s have ameliorative effects on protein misfolding diseases. This review describes structural features and cellular functions of Hsp70s that are relevant to design of Hsp70-targeted drugs.