Misfolded client proteins

Misfolded client proteins refer to a broad class of proteins that require the assistance of molecular chaperones, most notably Heat Shock Protein 90 (Hsp90) and Hsp70, to maintain their functional three-dimensional conformation. These clients include a wide array of signaling kinases, steroid receptors, and transcription factors that are essential for cellular growth and survival. In the context of disease, particularly oncology, many client proteins are mutated or overexpressed (e.g., HER2, BRAF, BCR-ABL), making the cell hypersensitive to chaperone inhibition. When the chaperone-client interaction is disrupted by drugs, these proteins fail to fold correctly, become unstable, and are subsequently targeted for degradation via the ubiquitin-proteasome pathway. This mechanism allows for the simultaneous depletion of multiple oncogenic drivers, though it also presents challenges regarding systemic toxicity due to the essential nature of many client proteins in normal physiology.

Other names

Hsp90 client proteinsChaperone clientsUnfolded proteinsProteotoxic substrates

Inhibition of molecular chaperones (e.g., Hsp90) leads to the destabilization, misfolding, and proteasomal degradation of client proteins; Proteasome inhibition leads to the toxic accumulation of misfolded proteins inducing apoptosis.