Heat shock protein HSP 90-alpha (HSP90AA1) (HSP90AA1)

Heat shock protein HSP 90-alpha (HSP90AA1) is a highly conserved molecular chaperone that utilizes ATPase activity to facilitate the folding, maturation, and stabilization of numerous client proteins essential for cellular signaling (UniProt P07900). It plays a pivotal role in maintaining the proteome, particularly under stress conditions, by preventing protein aggregation and assisting in the maturation of kinases, transcription factors, and steroid receptors (PubMed: 27513134). In oncological contexts, HSP90 is frequently overexpressed, where it stabilizes mutated or overexpressed oncoproteins like HER2, BRAF, and BCR-ABL, thereby promoting tumor cell survival and proliferation (PubMed: 23027834). Therapeutic targeting of HSP90 involves small-molecule inhibitors that bind to its N-terminal ATP-binding pocket, triggering the ubiquitin-mediated proteasomal degradation of these client proteins. However, the clinical development of HSP90 inhibitors has been significantly challenged by safety concerns, including hepatotoxicity and ocular disturbances, as well as off-target effects resulting from the simultaneous inhibition of multiple HSP90 isoforms or other human proteins (PubMed: 28273103).

Other names

HSP90AHSP86LAP-2HSPNHSP90NHeat shock 90kDa protein 1, alpha

HSP90 inhibitors bind to the N-terminal ATP-binding pocket of the HSP90AA1 protein, inhibiting its ATPase activity and preventing the conformational changes required for client protein maturation, leading to proteasomal degradation of client proteins.