Heat shock protein 90 (HSP90) is a chaperone with vital roles in regulating proteostasis, long recognized for its function in protein folding and maturation. A view is emerging that identifies HSP90 not as one protein that is structurally and functionally homogeneous but, rather, as a protein that is shaped by its environment. In this Review, we discuss evidence of multiple structural forms of HSP90 in health and disease, including homo-oligomers and hetero-oligomers, also termed epichaperomes, and examine the impact of stress, post-translational modifications and co-chaperones on their formation. We describe how these variations influence context-dependent functions of HSP90 as well as its interaction with other chaperones, co-chaperones and proteins, and how this structural complexity of HSP90 impacts and is impacted by its interaction with small molecule modulators. We close by discussing recent developments regarding the use of HSP90 inhibitors in cancer and how our new appreciation of the structural and functional heterogeneity of HSP90 invites a re-evaluation of how we discover and implement HSP90 therapeutics for disease treatment.
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This work was supported by the National Cancer Institute (NCI) Intramural Program and the National Institutes of Health (NIH) Extramural Program (R01 CA172546, P01 CA186866, R56 AG061869, R01 AG067598, P01 AG014449, P01 AG017617, R01 AG074004, R56 AG072599, RF1 AG071805 and P30 CA08748), The Breast Cancer Fund, Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center (MSKCC).
Memorial Sloan Kettering Cancer Center (MSKCC) holds the intellectual rights to the epichaperome portfolio. G.C. and C.S.D. are inventors on patents related to heat shock protein 90 (HSP90) composition of matter and methods of use. All other authors declare no competing interests.
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Nature Reviews Molecular Cell Biology thanks Matthias Mayer, Patricija van Oosten-Hawle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Chiosis, G., Digwal, C.S., Trepel, J.B. et al. Structural and functional complexity of HSP90 in cellular homeostasis and disease. Nat Rev Mol Cell Biol 24, 797–815 (2023). https://doi.org/10.1038/s41580-023-00640-9
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