Heat shock protein 90 (HSP90) is a molecular chaperone that is conserved from bacteria to humans and facilitates the maturation of substrates (or clients) that are involved in many different cellular pathways. HSP90 clients include, among others, kinases, transcription factors, steroid hormone receptors and E3 ubiquitin ligases.
The highly dynamic conformational changes in the HSP90 dimer are regulated by a set of co-chaperones that bind to HSP90, often in different phases of its ATPase cycle. Co-chaperones modulate the rate of ATP hydrolysis by HSP90, stabilize certain conformational states or are involved in client recruitment. Some co-chaperones introduce asymmetry in the symmetric HSP90 dimer.
HSP90 binds to clients in different conformations. Novel insights into client maturation have revealed that clients form contacts mainly with the middle domain of HSP90, but also make contacts with the amino-terminal and carboxy-terminal domains.
HSP90 clients are functionally and structurally diverse. Within this broad range of clients, intrinsic instability and low folding cooperativity seem to dictate the requirement for the chaperone activity of HSP90.
The pleiotropic effects of HSP90 on diverse client proteins means that HSP90 is implicated in many diseases, most prominently cancer, neurodegenerative diseases and infectious diseases that are caused by viruses and protozoa.
A number of HSP90 inhibitors have been identified that target the ATP-binding site or the carboxy-terminal domain. A number of these are currently being evaluated in clinical trials.
The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.
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This work was supported by the SFB1035 and IMPRS-LS grants. Furthermore, the authors thank F. Hagn, T. Madl and S. Lagleder for providing access to unpublished structural data. The authors also acknowledge all of the work that could not be cited within the scope of this article.
The authors declare no competing financial interests.
Proteins that form a complex with protein substrates to influence structural rearrangements, which are required for the activation or folding of the substrate. Chaperones dissociate from their substrates when this process is complete.
Maintenance of the integrity of the cellular protein network; it is also referred to as protein homeostasis.
Substrates that physically interact with heat shock protein 90 (HSP90). The activity of clients is influenced by HSP90.
- Heat shock response
Regulation of gene expression in response to high temperatures.
Non-client proteins that physically interact with a chaperone protein and assist the chaperone in its function to fold or activate other proteins.
(Heat shock protein 70). A family of 70 kDa ATP-dependent molecular chaperones with constitutively expressed and stress-induced members. HSP70 proteins bind to linear sequences in unfolded segments of proteins. Several co-chaperones (including ATPase accelerators, nucleotide exchange factors, and so on) regulate its function.
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Schopf, F., Biebl, M. & Buchner, J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol 18, 345–360 (2017). https://doi.org/10.1038/nrm.2017.20
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