Functional and physical interaction between yeast Hsp90 and Hsp70

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Abstract

<p id="d7615407e248">The Hsp90 molecular chaperone remodels and activates a large variety of client proteins. Its activity requires collaboration with the more than 25 Hsp90 cochaperone proteins, including the Hsp70 chaperone. In higher eukaryotes, Hsp90 collaborates with Hsp70 through a bridging protein, the Hop cochaperone. We show that yeast Hsp90 (Hsp82) and Hsp70 (Ssa1) directly interact in vitro in the absence of yeast Hop (Sti1) and identify a region in the middle domain of yeast Hsp90 that is important for interaction with Hsp70. This region of Hsp90 is also important for interactions with several cochaperones and client proteins, suggesting that collaboration between Hsp70 and Hsp90 in protein remodeling may be modulated through competition between Hsp70 and Hsp90 cochaperones for the interaction surface. </p><p class="first" id="d7615407e251">Heat shock protein 90 (Hsp90) is a highly conserved ATP-dependent molecular chaperone that is essential in eukaryotes. It is required for the activation and stabilization of more than 200 client proteins, including many kinases and steroid hormone receptors involved in cell-signaling pathways. Hsp90 chaperone activity requires collaboration with a subset of the many Hsp90 cochaperones, including the Hsp70 chaperone. In higher eukaryotes, the collaboration between Hsp90 and Hsp70 is indirect and involves Hop, a cochaperone that interacts with both Hsp90 and Hsp70. Here we show that yeast Hsp90 (Hsp82) and yeast Hsp70 (Ssa1), directly interact in vitro in the absence of the yeast Hop homolog (Sti1), and identify a region in the middle domain of yeast Hsp90 that is required for the interaction. In vivo results using Hsp90 substitution mutants showed that several residues in this region were important or essential for growth at high temperature. Moreover, mutants in this region were defective in interaction with Hsp70 in cell lysates. In vitro, the purified Hsp82 mutant proteins were defective in direct physical interaction with Ssa1 and in protein remodeling in collaboration with Ssa1 and cochaperones. This region of Hsp90 is also important for interactions with several Hsp90 cochaperones and client proteins, suggesting that collaboration between Hsp70 and Hsp90 in protein remodeling may be modulated through competition between Hsp70 and Hsp90 cochaperones for the interaction surface. </p>

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The HSP90 chaperone machinery

Florian H. Schopf, Maximilian Biebl, Johannes Buchner (2017)

The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis. Recent progress has shed light on the interactions of HSP90 with its clients and co-chaperones, and on their functional implications. This opens up new avenues for the development of drugs that target HSP90, which could be valuable for the treatment of cancers and protein-misfolding diseases.

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Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex.

Maruf M. U. Ali, S. Mark Roe, Cara Vaughan … (2006)

Hsp90 (heat shock protein of 90 kDa) is a ubiquitous molecular chaperone responsible for the assembly and regulation of many eukaryotic signalling systems and is an emerging target for rational chemotherapy of many cancers. Although the structures of isolated domains of Hsp90 have been determined, the arrangement and ATP-dependent dynamics of these in the full Hsp90 dimer have been elusive and contentious. Here we present the crystal structure of full-length yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1. The structure reveals the complex architecture of the 'closed' state of the Hsp90 chaperone, the extensive interactions between domains and between protein chains, the detailed conformational changes in the amino-terminal domain that accompany ATP binding, and the structural basis for stabilization of the closed state by p23/Sba1. Contrary to expectations, the closed Hsp90 would not enclose its client proteins but provides a bipartite binding surface whose formation and disruption are coupled to the chaperone ATPase cycle.

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Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone.

Chrisostomos Prodromou, S.Mark Roe, Ronan O'Brien … (1997)

Hsp90 molecular chaperones in eukaryotic cells play essential roles in the folding and activation of a range of client proteins involved in cell cycle regulation, steroid hormone responsiveness, and signal transduction. The biochemical mechanism of Hsp90 is poorly understood, and the involvement of ATP in particular is controversial. Crystal structures of complexes between the N-terminal domain of the yeast Hsp90 chaperone and ADP/ATP unambiguously identify a specific adenine nucleotide binding site homologous to the ATP-binding site of DNA gyrase B. This site is the same as that identified for the antitumor agent geldanamycin, suggesting that geldanamycin acts by blocking the binding of nucleotides to Hsp90 and not the binding of incompletely folded client polypeptides as previously suggested. These results finally resolve the question of the direct involvement of ATP in Hsp90 function.