Hsp70Hsp90

Hsp70 and Hsp90 are two major families of molecular chaperones that play essential roles in protein folding, stabilization, and activation. They are highly conserved across species and form key components of the cellular proteostasis network. While structurally distinct, they often work in concert with a range of cochaperones to guide client proteins through successive folding and maturation steps.

Hsp70 proteins bind short, hydrophobic regions of unfolded or partially folded polypeptides. In the ATP-bound state, Hsp70 has low affinity for substrates, allowing access and release; hydrolysis to ADP increases substrate affinity, stabilizing bound folding intermediates. Nucleotide exchange factors and J-domain cochaperones (Hsp40 family) regulate the ATPase cycle and substrate capture. This cycle prevents aggregation, assists in proper folding, and can direct misfolded proteins toward degradation pathways when necessary.

Hsp90 proteins act later in the folding pathway, specializing in signaling proteins, kinases, transcription factors, and steroid receptors. Hsp90 operates as a dimer with an ATPase-dependent cycle that drives conformational changes essential for client activation. Cochaperones such as p23, Hop/Sti1, Aha1, and Cdc37 modulate the timing and specificity of client maturation. Hsp90’s client repertoire is enriched for signaling and regulatory proteins, many of which depend on its activity for functional conformation.

In cells, Hsp70 and Hsp90 pathways intersect, with Hsp70 delivering clients to Hsp90 through a network of cochaperones. The activity of both systems is upregulated during stress by heat shock factors, reflecting their role in protecting cells from proteotoxic stress. Clinically, Hsp90 inhibitors and, more broadly, chaperone-targeting strategies are explored in cancer and neurodegenerative disease research due to their influence on essential client proteins.