Heat shock protein 90–Cell division cycle 37 hetero-chaperone complex (Hsp90–Cdc37 complex)

The Heat shock protein 90–Cell division cycle 37 (Hsp90–Cdc37) hetero-chaperone complex is a specialized molecular assembly essential for the maturation and stability of a vast array of protein kinases. Within this complex, Hsp90 serves as the core ATP-dependent chaperone, while Cdc37 acts as a dedicated co-chaperone adaptor that specifically recognizes and recruits kinase clients to the Hsp90 machinery [1, 13, 14]. This interaction is critical for the functional activation of approximately 60% of the human kinome, including key regulators of cell growth and survival such as Akt, Raf-1, and CDK4 [8, 14]. In pathological states like cancer, the complex is often overexpressed or hyperactivated, providing a survival advantage to malignant cells by stabilizing oncogenic kinases [4, 9, 14]. In neurodegenerative diseases, it is implicated in the regulation of kinases that drive toxic protein aggregation [2, 3]. Therapeutic strategies targeting this complex primarily focus on disrupting the protein-protein interaction (PPI) between Hsp90 and Cdc37 using small molecules or natural products like celastrol and withaferin A [2, 14]. Unlike broad-spectrum Hsp90 inhibitors, these PPI disruptors offer a more selective mechanism by specifically targeting kinase-dependent pathways and avoiding the induction of a systemic heat shock response [1, 14, 15]. By preventing the recruitment of kinases to the chaperone, these agents trigger the selective degradation of pathogenic kinases via the ubiquitin-proteasome pathway [1, 14].

Other names

Hsp90/Cdc37 complexp50/Cdc37-Hsp90 complexHsp90-Cdc37 chaperone systemHsp90-Cdc37-kinase complex

Disruption of the protein-protein interaction between Hsp90 and Cdc37, preventing the recruitment and stabilization of client kinases and leading to their ubiquitin-mediated proteasomal degradation [1, 14, 15].