Hsp70Hsc70

Hsp70 and Hsc70 refer to members of the Hsp70 (heat shock protein 70) chaperone family. The terms are used to distinguish inducible and constitutive cytosolic forms, though the family also includes organelle-specific members. In humans, the constitutive cytosolic Hsc70 is encoded by HSPA8, while inducible cytosolic Hsp70 isoforms include HSPA1A and HSPA1B (often collectively called Hsp70 or Hsp72). Other organelle-specific members include BiP/GRP78 (HSPA5) in the endoplasmic reticulum and mitochondrial Hsp70s (e.g., mortalin, HSPA9).

Structure and mechanism

Hsp70 proteins share a characteristic architecture with an N-terminal ATPase domain and a C-terminal substrate-binding domain, connected by a flexible linker. The substrate-binding domain contains a lid that modulates access to bound polypeptides. In the ATP-bound state, Hsp70 exhibits relatively low affinity for substrates; upon adenosine triphosphate hydrolysis, often stimulated by co-chaperones, affinity increases, allowing binding and release of unfolded or partially folded polypeptides. Nucleotide exchange factors facilitate the return to the ATP-bound state, enabling substrate cycling.

Function and co-chaperones

Hsp70 chaperones assist de novo protein folding, prevent aggregation of unfolded proteins, help translocate proteins across membranes into organelles, and participate in protein quality control. They operate in collaboration with Hsp40/DNAJ co-chaperones that recruit substrates and stimulate ATP hydrolysis, and with nucleotide exchange factors (such as BAG family proteins or GrpE in bacteria) that promote ADP-ATP exchange and substrate release.

Clinical relevance

Hsp70/Hsc70 proteins are central to cellular proteostasis and are upregulated during stress. They are implicated in cancer, neurodegenerative diseases, and aging. Because they support protein folding and survival of stressed cells, they are targets of research aimed at modulating chaperone activity, either to promote proteostasis or to sensitize diseased cells.