Heat shock protein 90 (Hsp90) chaperone machinery (Hsp90)

Heat shock protein 90 (Hsp90) is a ubiquitous and highly conserved molecular chaperone that plays a central role in maintaining protein homeostasis by assisting in the folding, stabilization, and activation of a vast array of "client" proteins (Schopf et al., 2017, Nat Rev Mol Cell Biol; Whitesell & Lindquist, 2005, Nat Rev Cancer). The Hsp90 chaperone machinery functions as a dynamic multi-protein complex, utilizing ATP hydrolysis to drive conformational changes facilitated by various co-chaperones such as Cdc37, Hop, and p23 (Taipale et al., 2010, Nat Rev Mol Cell Biol). In many diseases, particularly cancer, Hsp90 is hijacked to stabilize mutated, chimeric, or overexpressed oncogenic signaling proteins, including HER2, BCR-ABL, and BRAF, which are essential for tumor growth and survival (Neckers & Workman, 2012, Clin Cancer Res; Trepel et al., 2010, Nat Rev Cancer). Inhibition of Hsp90 leads to the destabilization and subsequent degradation of these client proteins via the ubiquitin-proteasome pathway, providing a unique mechanism to simultaneously disrupt multiple signaling pathways (Isaacs et al., 2003, Cancer Cell). Beyond oncology, Hsp90 is involved in the maturation of viral proteins and the management of protein aggregates in neurodegenerative disorders like Alzheimer's and Parkinson's disease (Geller et al., 2012, Genes Dev; Lackie et al., 2017, Rev Physiol Biochem Pharmacol). While several Hsp90 inhibitors, such as tanespimycin and ganetespib, have reached clinical trials, their development has been complicated by safety concerns including hepatotoxicity and ocular disturbances (Butler et al., 2015, Nat Rev Cancer; Jhaveri et al., 2014, J Hematol Oncol).

Other names

HSP90Heat shock protein 90HSP90AA1HSP90AB1HSP90B1TRAP1HSP90 alphaHSP90 beta90 kDa heat shock proteinHsp90 complex

Inhibition of the N-terminal ATP-binding pocket of Hsp90, which prevents the ATPase-dependent chaperone cycle and leads to the ubiquitin-proteasome-mediated degradation of oncogenic client proteins (Whitesell & Lindquist, 2005, Nat Rev Cancer).