Heat shock protein 90kDa alpha class A member 1 (HSP90AA1) (HSP90AA1)

Heat shock protein 90kDa alpha class A member 1 (HSP90AA1) is a highly conserved molecular chaperone that plays a critical role in the folding, stabilization, and activation of a wide array of client proteins (UniProt P07900). These clients include many essential signaling kinases, transcription factors, and steroid receptors that regulate cell growth and survival (PubMed: 28273103). In many cancers, HSP90AA1 is overexpressed and serves to stabilize mutated or overexpressed oncogenic proteins, such as HER2 and BRAF, allowing tumor cells to thrive under stressful conditions (NCBI Gene: 3320). Consequently, HSP90AA1 has emerged as a significant therapeutic target in oncology, as its inhibition can simultaneously disrupt multiple signaling pathways (PubMed: 23548286). Drugs targeting this protein typically bind to its N-terminal ATP-binding pocket, inhibiting its ATPase activity and triggering the degradation of its client proteins (PubChem: 11485656). While clinical trials have demonstrated the potential of HSP90 inhibitors like Ganetespib, challenges such as off-target toxicities and the induction of compensatory heat shock responses remain (PubMed: 26916316). Beyond cancer, HSP90AA1 is also being investigated for its role in neurodegenerative diseases and viral infections where protein homeostasis is compromised.

Other names

HSP90AHSP90alphaHSPCAHSPNLAP2HSP86Hsp89Heat shock 90kDa protein 1, alpha

Inhibition of the ATPase activity of HSP90, which prevents the chaperone from folding and stabilizing its client proteins, leading to their degradation via the ubiquitin-proteasome pathway (PubMed: 23548286).