Two chaperone sites in Hsp90 differing in substrate specificity and ATP dependence
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The abundant molecular chaperone Hsp90 is a key regulator of protein structure in the cytosol of eukaryotic cells. Although under physiological conditions a specific subset of proteins is substrate for Hsp90, under stress conditions Hsp90 seems to perform more general functions. However, the underlying mechanism of Hsp90 remained enigmatic. Here, we analyzed the function of conserved Hsp90 domains. We show that Hsp90 possesses two chaperone sites located in the N- and C-terminal fragments, respectively. The C-terminal fragment binds to partially folded proteins in an ATP-independent way potentially regulated by cochaperones. The N-terminal domain contains a peptide binding site that seems to bind preferentially peptides longer than 10 amino acids. Peptide dissociation is induced by ATP binding. Furthermore, the antitumor drug geldanamycin both inhibits the weak ATPase of Hsp90 and stimulates peptide release. We propose that the existence of two functionally different chaperone sites together with a substrate-selecting set of cochaperones allows Hsp90 to guide the folding of a subset of target proteins and, at the same time, to exhibit general chaperone functions.
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The ATPase cycle is relatively slow, yeast Hsp90 hydrolysing an ATP molecule every 1-2 minutes.
“The ATPase cycle is relatively slow, yeast Hsp90 hydrolysing an ATP molecule every 1-2 minutes28,29.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [29]
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“Importantly, many client - interacting regions have been identified in the NTD of Hsp90s, including residues that directly form the lid region (70–72).”
- Authors
- Scheibel, T., Weikl, T., & Buchner, J.
- Affiliations
- University of Regensburg (DE)
- Institut für Biophysik und Physikalische Biochemie, Universität Regensburg, 93040 Regensburg, Germany
- ORCID
- Scheibel, Thomas
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-02-17
- Volume
- 95
- Issue
- 4
- Pages
- 1495-1499
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC19060
- OpenAlex
- W1983665072
- Cited by
- 243
- References
- 31
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 1 · 2015: 4 · 2014: 2 · 2013: 5 · 2012: 15
- FWCI
- 9.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ERef Bayreuth (University of Bayreuth) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- HSP90, molecular chaperones, substrate specificity, ATP dependence, peptide binding site, co-chaperones, geldanamycin, ATPase activity, protein folding, partially folded proteins, N-terminal domain, C-terminal fragment
- MeSH terms
- Adenosine Triphosphate, Binding Sites, Citrate (si)-Synthase, Cloning, Molecular, Fungal Proteins, Insulin, Peptides, Protein Binding, Protein Denaturation, Saccharomyces cerevisiae, Substrate Specificity, Protein Folding, Molecular Chaperones, HSP90 Heat-Shock Proteins
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