The Charged Linker Modulates the Conformations and Molecular Interactions of Hsp90
Open accessAbstract
The molecular chaperone Hsp90 supports the functional activity of specific substrate proteins (clients). For client processing, the Hsp90 dimer undergoes a series of ATP‐driven conformational rearrangements. Flexible linkers connecting the three domains of Hsp90 are crucial to enable dynamic arrangements. The long charged linker connecting the N‐terminal (NTD) and middle (MD) domains exhibits additional functions in vitro and in vivo. The structural basis for these functions remains unclear. Here, we characterize the conformation and dynamics of the linker and NTD−MD domain interactions by NMR spectroscopy. Our results reveal two regions in the linker that are dynamic and exhibit secondary structure conformation. We show that these regions mediate transient interactions with strand β8 of the NTD. As a consequence, this strand detaches and exposes a hydrophobic surface patch, which enables binding to the p53 client. We propose that the charged linker plays an important regulatory role by coupling the Hsp90 NTD−MD arrangement with the accessibility of a client binding site on the NTD.
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p53 shows the strongest effects to the NTD-MD interface and the linker region.
“GR and MR both show notable effects with the CTD helix Cα2, which projects toward the MD (Fig. 6, B and D), while p53 shows the strongest effects to the NTD-MD interface and the linker region, consistent with previous studies (43, 53).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [53]
p53-DBD binds to the NTD-MD interface, involving sites of the NTD that are regulated by the charged linker connecting the two domains.
“The p53-DBD binds to the NTD-MD interface, involving sites of the NTD that are regulated by the charged linker connecting the two domains (53).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [53]
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References 47 · Cited by 30
Research works printed but not linked: 2
- M. Jahn, A. Rehn, B. Pelz, B. Hellenkamp, K. Richter, M. Rief, J. Buchner, T. Hugel, Proc. Natl. Acad. Sci. USA 2014, 111, 17881– 17886; 25468961 PMC4273377
- [31]D. S. Wishart, C. G. Bigam, A. Holm, R. S. Hodges, B. D. Sykes, J. Biomol. NMR 1995, 5, 67– 81. 7881273
- Authors
- López, A., Elimelech, A. R., Klimm, K., & Sattler, M.
- Affiliations
- Center for Integrated Protein Science Munich (DE)
- Corresponding author
- Sattler, Michael
- Venue
- ChemBioChem
- Publisher
- Wiley
- Published
- 2020-12-09
- Volume
- 22
- Issue
- 6
- Pages
- 1084-1092
- ISSN
- 1439-4227 (ISSN-L)
- 1439-7633
- PMC
- PMC8048802
- OpenAlex
- W3097536747
- Cited by
- 30
- References
- 47
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 9 · 2021: 6 · 2020: 1
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- ChemBioChem (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion, cc-by-nc-nd)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 1035, 201302640)
- 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, N-terminal domain, middle domain, domain interactions, secondary structure, p53 binding
- MeSH terms
- Protein Domains, Protein Conformation, beta-Strand, Amino Acid Sequence, Binding Sites, Calorimetry, Recombinant Proteins, Saccharomyces cerevisiae, Sequence Alignment, HSP90 Heat-Shock Proteins, Nuclear Magnetic Resonance, Biomolecular, Molecular Dynamics Simulation
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