Structural analysis of the interaction between Hsp90 and the tumor suppressor protein p53
Abstract
In eukaryotes, the essential dimeric molecular chaperone Hsp90 is required for the activation and maturation of specific substrates such as steroid hormone receptors, tyrosine kinases and transcription factors. Hsp90 is involved in the establishment of cancer and has become an attractive target for drug design. Here we present a structural characterization of the complex between Hsp90 and the tumor suppressor p53, a key mediator of apoptosis whose structural integrity is crucial for cell-cycle control. Using biophysical methods, we show that the human p53 DNA-binding domain interacts with multiple domains of yeast Hsp90. p53 binds to the Hsp90 C-terminal domain in its native-like state in a charge-dependent manner, but it also associates weakly with binding sites in the middle and the N-terminal domains. The fine-tuned interplay between several Hsp90 domains provides the interactions required for efficient chaperoning of p53.
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In the absence of nucleotides, all clients show similar affinities in the low micromolar range for Hsp90.
“In the absence of nucleotides, all clients show similar affinities in the low micromolar range for Hsp90 (Table 1), consistent with previous studies (16, 20, 48).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [20]
Electrostatic interactions with the disordered C-terminal extension contribute to p53 binding.
“In addition, electrostatic interactions with the disordered C-terminal extension contribute to p53 binding (20).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [20]
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- Authors
- Hagn, F., Lagleder, S., Retzlaff, M., Rohrberg, J., Demmer, O., Richter, K., Buchner, J., & Kessler, H.
- Affiliations
- Center for Integrated Protein Science Munich (DE)
- Harvard University (US)
- King Abdulaziz University (SA)
- Corresponding author
- Kessler, Horst
- Venue
- Nature Structural & Molecular Biology
- Published
- 2011-09-04
- Volume
- 18
- Issue
- 10
- Pages
- 1086-1093
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2092972919
- Cited by
- 127
- References
- 64
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 9 · 2020: 10 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 8 · 2015: 13 · 2014: 10 · 2013: 15 · 2012: 6
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- HSP90, p53, protein-protein interaction, molecular chaperones, DNA-binding domain, tumor suppressor, cancer drug targets
- MeSH terms
- Binding Sites, Humans, Models, Molecular, Protein Binding, Protein Conformation, Tumor Suppressor Protein p53, HSP90 Heat-Shock Proteins, Nuclear Magnetic Resonance, Biomolecular
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