Hsp90

HSP90, or heat shock protein 90, is a highly conserved molecular chaperone that assists in the folding, stabilization, and maturation of a large set of client proteins. In humans, there are several isoforms: the cytosolic HSP90α (HSP90AA1) and HSP90β (HSP90AB1), the mitochondrial member TRAP1, and the endoplasmic reticulum–localized GRP94 (HSP90B1). These forms share a common architecture but differ in cellular localization and specific client repertoires.

HSP90 proteins have a modular structure consisting of an N-terminal ATP-binding domain, a middle domain that interacts with clients, and a C-terminal dimerization domain that includes the MEEVD motif for binding co-chaperones. The chaperone cycle is driven by ATP binding and hydrolysis, which triggers conformational changes that facilitate client protein folding and activation. HSP90 functions as a dimer and operates within multi-chaperone complexes.

Functionally, HSP90 stabilizes and activates a broad range of client proteins, including kinases, transcription factors, and steroid hormone receptors. Through these actions, it influences cell signaling, growth, and stress responses. Because many oncogenic and signaling proteins rely on HSP90 for stability, the chaperone is a focal point in cancer biology.

Co-chaperones regulate HSP90 activity and specificity. The HSP70–HSP90 system, via STIP1/HOP, coordinates client transfer; p23 stabilizes the ATP-bound complex; Aha1 enhances ATP hydrolysis; Cdc37 targets kinases; and CHIP can tag misfolded clients for degradation.

Clinically, HSP90 is a drug target in cancer therapy. N-terminal inhibitors such as geldanamycin and its derivative 17-AAG disrupt ATP binding, while second-generation inhibitors like ganetespib and other compounds have advanced in trials. C-terminal inhibitors, including novobiocin derivatives, provide alternative approaches. Inhibition can trigger client degradation but may also cause toxicity and compensatory responses.