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Review
. 2018 Aug 29;19(9):2560.
doi: 10.3390/ijms19092560.

The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease

Abdullah Hoter  1   2 , Marwan E El-Sabban  3 , Hassan Y Naim  4
Affiliations
Review

The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease

Abdullah Hoter et al. Int J Mol Sci. .

Abstract

The mammalian HSP90 family of proteins is a cluster of highly conserved molecules that are involved in myriad cellular processes. Their distribution in various cellular compartments underlines their essential roles in cellular homeostasis. HSP90 and its co-chaperones orchestrate crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis. Conversely, HSP90, and its secreted forms, contribute to the development and progress of serious pathologies, including cancer and neurodegenerative diseases. Therefore, targeting HSP90 is an attractive strategy for the treatment of neoplasms and other diseases. This manuscript will review the general structure, regulation and function of HSP90 family and their potential role in pathophysiology.

Keywords: GRP94; HSP90; TRAP1; molecular chaperones; pathophysiology; structure and function.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Domain structure of HSP90 family members in humans. The numbering 1–900 indicates the amino acid sequence. The lengths of HSP90α, HSP90β, GRP94, and TRAP1 are 732, 724, 704, and 803 amino acids, respectively. Below is shown a schematic representation of the domain structure of HSP90 isoforms together with the biological function of each domain.
Figure 2
Figure 2
Schematic representation of the ATPase cycle of HSP90. The open and closed conformations of HSP90 are depicted.
Figure 3
Figure 3
The mechanism of protein folding by HSP90 [44]. (I) The client protein either mis-folded protein or nascent polypeptide is bound by Hsp70/Hsp40/ADP complex to be protected from potential aggregation [102]; (II) The protein complex formed is further stabilized by Hsp70-interacting protein (HIP) or Bcl2 which support the change of ADP to ATP [103]; (III) HSP90 binds the client protein harboured by the Hsp70/Hsp40 protein complex to start its action; (IV) The interaction between HSP90 and HSP70 is facilitated by the adaptor protein, HOP/Sti1 (Hsp90–Hsp70 organizing protein) [104]. Importantly, additional co-chaperone known as Cdc37 (cell-division-cycle 37 homologue) or p50 is needed for loading client kinases onto HSP90 [105]; (V) As the client protein is loaded, other co-chaperones, immunophilins like (FKBP51, FKBP52) are added to the HSP90 homodimer forming an activated heteroprotein complex while the HSP70, HIP and HOP are released [106]; (VI) Binding of ATP to the NTD of HSP90 in the heteroprotein complex switches the HSP90 from the “open state” to the “closed state” [107]. Various inhibitors of HSP90 can act at this stage by competing with ATP for the NTD binding site consequently resulting in protein degradation by proteasome [101]; (VII) If no inhibitors interfere with the folding cycle, association of other co-chaperones occurs including p23 and Aha1 (activator of Hsp90 ATPase homologue 1); (VIII) Binding of Aha1, not shown in the diagram, to the MD of HSP90 induces ATP hydrolysis and supports folding of the bound client, as well as enhances the release of immunophilins and co-chaperones [96].
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