Hsp90

It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.

[3] As their name implies, heat shock proteins protect cells when stressed by elevated temperatures.

[8] The α- and the β-forms are thought to be the result of a gene duplication event that occurred millions of years ago.

[18][25] The C-terminal domain possesses an alternative ATP-binding site, which becomes accessible when the N-terminal Bergerat pocket is occupied.

[26][27] At the very C-terminal end of the protein is the tetratricopeptide repeat (TPR) motif recognition site, the conserved MEEVD pentapeptide, that is responsible for the interaction with co-factors such as the immunophilins FKBP51 and FKBP52, the stress induced phosphoprotein 1 (Sti1/Hop), cyclophilin-40, PP5, Tom70, and many more.

[31] Antitumor drugs targeting this section of Hsp90 include the antibiotics geldanamycin,[11][32] herbimycin, radicicol, deguelin,[33] derrubone,[34] macbecin,[35] and beta-lactams.

Thus, ATP hydrolysis drives what is commonly referred to as a “pincer-type” conformational change in the protein binding site.

[39] The ability of Hsp90 to clamp onto proteins allows it to perform several functions including assisting folding, preventing aggregation, and facilitating transport.

[40] Furthermore, Hsp90 has been shown to suppress the aggregation of a wide range of "client" or "substrate" proteins and hence acts as a general protective chaperone.

[44] Eukaryotic proteins that are no longer needed or are misfolded or otherwise damaged are usually marked for destruction by the polyubiquitation pathway.

[50][51] In the absence of the steroid hormone cortisol, GR resides in the cytosol complexed with several chaperone proteins including Hsp90 (see figure to the right).

A second role of Hsp90 is to bind immunophilins (e.g., FKBP52) that attach the GR complex to the dynein protein trafficking pathway, which translocates the activated receptor from the cytoplasm into the nucleus.

Hsp90 is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone,[53] androgen,[54] estrogen,[55] and progesterone.

[59][15][60] Interestingly, the disruption of HSP90 with nano-therapeutics has been implicated in targeting drug-induced resistance and relieves the suppression of Natural Killer (NK) immune cells in breast cancer.

[62] Hsp90 is also required for induction of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS).

[24] Both are important for de novo angiogenesis that is required for tumour growth beyond the limit of diffusion distance of oxygen in tissues.

[63] Together with its co-chaperones, Hsp90 modulates tumour cell apoptosis "mediated through effects on AKT,[23] tumor necrosis factor receptors (TNFR) and nuclear factor-κB (NF-κB) function.".

[64] Also, Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis.

Hsp90 plays apparently conflicting roles in the cell, as it is essential for both the creation and the maintenance as well as the destruction of proteins.

[66] Prediction and validation of the immunodominant epitope/s of HSP90 beta protein has been demonstrated using sera from infertile women having anti-HSP90 autoantibodies.

A polyclonal antibody generated to the immunodominant epitope- EP6 confirms similar biochemical and cellular immunoreactivity as seen with the patients' sera with anti-HSP90 autoantibodies.

This inference is supported by the fact that the duplication is found in Giardia lamblia, one of the earliest branching eukaryotic species.

Domain structure of the yeast heat-inducible Hsp90. Top : Crystallographic structure of the dimeric Hsp90. [ 1 ] Bound ATP molecules are represented by space filling spheres. Bottom : 1D sequence of the yeast Hsp90. NTD= N-terminal domain (red), MD = middle domain (green), CTD = C-terminal domain (blue).
Crystallographic structure of the ATP binding pocket of Hsp90 where ATP is represented by a ball and stick figure (carbon atoms = grey, nitrogen = blue, oxygen = red, phosphorus = orange) and Hsp90 is depicted as a solid surface (negatively charged = red, positively charged = blue, electrostatically neutral = grey). [ 1 ]
Pincer movement of Hsp90 coupled to the ATPase cycle. NTD = N-terminal domain, MD = middle domain, CTD = C-terminal domain.
The Hsp90 chaperone cycle. X/Y represents an immature incompletely folded protein such a steroid receptor . Hsp40 , Hsp70 , and p23 are partner chaperones while Hop is a co-chaperone . Also, X-X represents a mature properly folded protein dimer.
Schematic diagram of the translocation of the glucocorticoid receptor (GR) from the cytoplasm into the nucleus assisted by Hsp90 (90). [ 48 ] In the cytoplasm, GR is complexed with Hsp90 and the immunophilin FKBP51 (51). Binding of hormone to GR causes a conformational change in the complex, which results in exchange of FKBP51 for FKBP52 (52). FKBP52 in turn binds the dynein (dyn) motor protein that attaches to the cytoskeleton and transports the GR complex into the nucleus. Once in the nucleus, the complex disassembles releasing GR, which dimerizes and binds to DNA where it facilitates transcription of DNA into mRNA .
HSP90-dependent cycle of steroid hormone receptor (SHR) activation. The minimal complex for SHR activation include HSP40 , HSP70 , HOP (Hsp organizing protein), HSP90 and p23 protein . Just after translation the steroid hormone receptor binds to HSP40 and HSP70 (top, left). Next, HOP protein (composed from TPR domains ) deliver it to HSP90. HOP mediates interaction between HSP70 and HSP90 through their C-terminal domains. This transfer takes place only if ADP is bound to HSP90. The exchange of ADP to ATP inside N-terminal pocket induces dissociation of HSP70 and its co-chaperones from the complex that associate then with p23 (via N-terminal side of HSP90 dimer) which prevents ATP hydrolysis, and immunophilins , which replaces HOP (right). At this point, if the chaperone binds geldanamycin , which mimics ADP binding, proteins p23 and HOP dissociate and CHIP , an E3 ubiquitin ligase, is attached to the complex and SHR receptor is being degraded through the proteasome-mediateted pathway (bottom, right). Immunophilins, FKBP51 and FKBP52 , are responsible for transportation of HSP90-SHR-ligand complexes along the microtubule fibers (additionally, dynamitin and dynein , the microtubule-associated proteins are involved in this process). Therefore, a translocation of hormones, p53 and probably other HSP90 substrate proteins within cytoplasm is fast and tightly controlled. ATP hydrolysis inside HSP90 nucleotide-binding pocket leads to the dissociation of the complex. Next, steroid hormone receptors dimerize and are translocated to the nucleus (bottom, left). Subsequently, SHR-hormone complexes bind to particular DNA sequences in the promoters of hormone-responsive genes to control their transcription . It should be stressed, that the movement of SHRs inside the nucleus is also HSP90- and ATP-dependent. But it is not known whether HSP90-HSP70-SHR complexes can be transmitted through the nuclear envelope pores as a whole or could shuttle between separate HSP90 molecular complexes on both sides of the nuclear envelope [ 49 ]