Trends in Biochemical Sciences
ReviewHsp90 interaction with clients
Section snippets
Hsp90 as a major chaperone: what does it do, and how?
Protein folding is a fundamental process that is essential for life. Proteins fold by embarking on folding pathways in which the protein adopts a 3D structure by nucleating around a hydrophobic core [1]. In the cell, this vital process is guarded by the proteostasis network, which controls protein fate at all stages and thereby prevents toxic side reactions (see Glossary) 2, 3, 4. Of particular importance is the shielding of hydrophobic residues, which are temporally exposed during initial
The nature of the Hsp90 substrate binding site
The current understanding of the nature of the Hsp90 substrate binding site is based on our structural understanding of Hsp90 as obtained by a range of biophysical techniques, and interaction studies with a range of natural clients, in particular kinases, steroid receptors, and the disordered protein Tau. We will elucidate the shape of the Hsp90 dimer and compare the regions to which the various studies mapped substrate binding.
Regulation of Hsp90
Hsp90 is not a passive protein scavenger; it is an ATP-controlled machine with a tightly regulated active cycle 5, 55, 56, 57. The N-terminal domain contains the pocket that binds and hydrolyses ATP [56]. The hydrolysis reaction requires a second conformational change in addition to C-terminal dimerisation. Instead of pointing in opposite directions, as in the open conformation, both N-terminal domains must connect to each other and provide a second, transient dimerisation interface [21].
The Hsp70/Hsp90 chaperoning cascade
The description of the substrate binding site of Hsp90 fits into a consistent picture of the action of chaperone cascades in the cell (Figure 2F):
- (i)
Hsp70 acts earlier than Hsp90. This is determined by the high affinity of Hsp70 for short, five-residue-long stretches containing typically three or more large hydrophobic or aromatic residues 10, 11. Such stretches are typically found inside the hydrophobic core of both folded proteins and late folding intermediates [15]. Thus, typically proteins
Concluding remarks
The client binding principle of Hsp90 relies on distributing hydrophobic contacts over a large surface [15]. Hsp90 does not have a binding pocket and cannot compete with Hsp70 for binding short hydrophobic stretches [15]. The Hsp90 ATPase, however, ensures that the client comes in from Hsp70 [50]. Significant overlap of the binding sites of folded GR and disordered Tau in the middle domain of Hsp90 suggests that highly diverse clients share the same binding principle (Figure 2BC).
In our view,
Acknowledgements
We thank Martina Radli, Tania Morán Luengo, and Melanie Balhuizen for comments on the manuscript. The work of the Rüdiger laboratory is funded by Marie-Curie Actions of the European Union (ITN-IDP ‘ManiFold’ and ITN ‘WntsApp’).
Glossary
- Aha1
- the Hsp90 co-chaperone that stimulates the ATP hydrolysis rate. Aha1 binds to Hsp90-N and Hsp90-M and competes with p23.
- Cdc37
- a kinase-specific substrate targeting factor of Hsp90. The human homologue is known as p50.
- Cdk4
- cyclin-dependent kinase 4 requires Hsp90 to reach the active state, like many other kinases.
- CHIP
- an E3 ubiquitin ligase, specifically interacts with both Hsp70 and Hsp90. It specifically targets the TPR motifs at the C terminus of the chaperone by its TPR domain and
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