Hsp90 Chaperones

Bettina K Zierer, Technische Universität München, Munich, Germany
Johannes Buchner, Technische Universität München, Munich, Germany

Published online: December 2012

DOI: 10.1002/9780470015902.a0024154

Heat shock protein 90 (Hsp90) is an abundant molecular chaperone especially important in the cytosol of eukaryotic cells. Its function is coupled to large conformational rearrangements within the dimer coupled to nucleotide binding. Hsp90 assists a large set of so-called ‘client’ proteins to stay folded or to achieve an active conformation. These client proteins include among others protein kinases and many transcription factors such as steroid hormone receptors. The function of the Hsp90 chaperone machinery itself is highly regulated on several levels. A large set of cochaperones as well as post-translational modifications help to fine-tune the conformational cycle. Inhibition of the low intrinsic adenosine triphosphatase (ATPase) activity of Hsp90 leads to destabilisation of its clients resulting in their degradation. As many of the clients are oncogenes, inhibition of Hsp90 is an important target in cancer therapy.

Key Concepts:

  • Hsp90 is an essential molecular chaperone in eukaryotes.
  • Hsp90 function is coupled to nucleotide-induced conformational changes.
  • Hsp90 stabilises the active state of a large set of clients.
  • Hsp90 function can be regulated via cochaperones or post-translational modifications.
  • Inhibition of Hsp90 is an anticancer strategy.

Keywords: Hsp90; chaperone; cochaperones; clients; conformational rearrangements; ATPase; post-translational modification

Figure 1. Structure of yeast Hsp90. Overlay of crystal structure of apo E. coli HtpG (pdb 2ioq) and closed structure of yeast Hsp90 (pdb 2cg9). In each structure one monomer is shown in grey and in the second one the N-domain is shown in blue, the M-domain in green and the C-domain in orange.
Figure 2. Conformational changes of Hsp90. (a) Conformational cycle of nucleotide-induced conformational changes. After fast ATP binding, conformational changes in the N-domain occur that are likely to involve movements of the ATP lid and release of the N-terminal segment from its interaction with the lid (I1). This reaction is disfavoured. Then N-terminal dimerisation leads to the formation of I2, in which the N-domains are dimerised. The interaction of the N-domain with the M-domain leads to the fully closed state, which commits the ATP for hydrolysis. Modified from Hessling et al. (2009) © Nature Publishing Group. (b) Structure of yeast Hsp90 N-domain (blue) in open (pdb 1AH6) and closed form (from pdb 2cg9). The lid segment (residues 94–125) is highlighted in red, the first eight amino acids in green and the bound nucleotide in yellow.
Figure 3. Structure of a TPR-domain. Shown is the crystal structure of the TPR2A module of yeast Sti1 (cyan) with bound MEEVD peptide (yellow) (from pdb 3uq3).
Figure 4. Model of the Hsp90 co-chaperone cycle. Sti1 binds to the C-domain of Hsp90 in the open conformation. For simplicity, Hsp70 is depicted to enter the cycle together with client protein after Sti1 is bound to Hsp90. Alternatively, Hsp70 could be already bound by Sti1. The second TPR-acceptor site of Hsp90 is then preferentially occupied by a PPIase, leading to an asymmetric Hsp90 complex. Hsp90 converts to the closed conformation after binding of ATP, release of Sti1 and binding of p23/Sba1. Another PPIase (dashed outline) can potentially bind to form the final complex together with Hsp90 and p23/Sba1. After ATP hydrolysis, p23/Sba1, the PPIase and the folded client are released from Hsp90. Modified from Li et al. (2011) © Nature Publishing Group.
Figure 5. Structures of known Hsp90 inhibitors: Radicicol, Geldanamycin, PU-H71 and Novobiocin.
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Related Sub-Topics:

Protein Structure | Protein Folding, Evolution and Degradation | Biomolecular Interactions | Proteins: Structure, Function, Metabolism
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Article Title: Hsp90 Chaperones
 
How to Cite close
Zierer, Bettina K, and Buchner, Johannes(Dec 2012) Hsp90 Chaperones. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024154]