Hsp70

Hsp70 refers to a family of highly conserved molecular chaperones that assist in protein folding, assembly, translocation, and quality control. They are ATP-dependent and operate through an ATPase cycle that regulates substrate binding and release.

All members share a two-domain organization: an N-terminal nucleotide-binding domain that hydrolyzes ATP and a substrate-binding domain that recognizes exposed hydrophobic regions on unfolded polypeptides. A C-terminal lid modulates access to the substrate, and cytosolic variants typically have an EEVD motif for co-chaperone interactions; organellar members carry targeting signals for mitochondria or the endoplasmic reticulum.

The chaperone cycle is controlled by co-chaperones. J-domain proteins (Hsp40) recruit substrates and stimulate ATPase activity, increasing substrate affinity. Nucleotide exchange factors promote ADP release and rebinding of ATP, resetting the cycle and enabling substrate release.

In cells, cytosolic Hsp70s aid in the folding of nascent chains, prevent aggregation, and facilitate refolding of stressed proteins. Mitochondrial Hsp70 assists import and folding within mitochondria, while the ER-resident BiP (Grp78) functions in protein translocation and ER proteostasis.

Hsp70 expression is upregulated by heat shock and other proteotoxic stresses via HSF1. The proteins are essential for cell viability and are implicated in diseases such as cancer and neurodegeneration. Because of their central role in proteostasis, Hsp70s are explored as therapeutic targets, with several inhibitors studied preclinically and clinically.