Hsc70

Heat shock cognate 70 kDa protein (Hsc70) is a constitutively expressed member of the Hsp70 family of molecular chaperones. In humans it is encoded by the HSPA8 gene. Hsc70 participates in protein homeostasis by assisting nascent and unfolded polypeptides to attain proper folding, preventing aggregation, and facilitating conformational changes required for activity. It also contributes to endocytosis by promoting disassembly of clathrin-coated vesicles in cooperation with co-chaperones such as auxilin.

Hsc70 operates through an ATPase-driven cycle. It contains an N-terminal nucleotide-binding domain and a C-terminal substrate-binding domain. Binding and hydrolysis of ATP regulate the affinity of Hsc70 for substrates: ATP binding lowers affinity, while hydrolysis to ADP increases substrate binding. Release of ADP and binding of new ATP reset the cycle. This cycle is coordinated by co-chaperones, including Hsp40 (DnaJ) proteins that stimulate ATP hydrolysis and nucleotide exchange factors (such as BAG family proteins) that promote ADP-ATP exchange. Hsc70 thus assists a wide range of client proteins through folding, stabilization, or translocation.

In addition to general folding duties, Hsc70 plays a key role in chaperone-mediated autophagy, recognizing substrate proteins bearing a specific motif and delivering them to the lysosomal receptor LAMP-2A for translocation and degradation. It also participates in the uncoating of clathrin during vesicle recycling, a function linked to its interaction with co-chaperones.

Localization of Hsc70 is primarily cytosolic, with presence in the nucleus as needed. As a housekeeping chaperone, it is essential for cellular proteostasis and viability, and dysregulation of its functions is implicated in various diseases, including neurodegenerative disorders and cancer.