A methylated lysine is a switch point for conformational communication in the chaperone Hsp90
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Methylation of a conserved lysine in C-terminal domain of the molecular chaperone Hsp90 was shown previously to affect its in vivo function. However, the underlying mechanism remained elusive. Through a combined experimental and computational approach, this study shows that this site is very sensitive to sidechain modifications and crucial for Hsp90 activity in vitro and in vivo. Our results demonstrate that this particular lysine serves as a switch point for the regulation of Hsp90 functions by influencing its conformational cycle, ATPase activity, co-chaperone regulation, and client activation of yeast and human Hsp90. Incorporation of the methylated lysine via genetic code expansion specifically shows that upon modification, the conformational cycle of Hsp90 is altered. Molecular dynamics simulations including the methylated lysine suggest specific conformational changes that are propagated through Hsp90. Thus, methylation of the C-terminal lysine allows a precise allosteric tuning of Hsp90 activity via long distances.
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K594 in the Cα2 element is an important switch point that allosterically regulates ATPase activity, dimer closing kinetics, co-chaperone modulation, and client maturation of Hsp90.
“It has been demonstrated that K594 in this element is an important switch point that allosterically regulates the ATPase activity, dimer closing kinetics, co-chaperone modulation, and client maturation of Hsp90 (59).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [59]
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Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network
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Inhibition of HSP90 S‐nitrosylation alleviates cardiac fibrosis via TGFβ/SMAD3 signalling pathway
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“For example, PTMs of HSP90 provide an important regulatory element, modulating co-chaperone and client protein binding 74 – 78 , ATPase activity 79 , conformational cycle 75,78 – 80 , turnover 81 , and small molecule af fi nity 12,39 .”
Hsp70 and Hsp90 post-translational modifications and translating the chaperone code
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Cellular Site-Specific Incorporation of Noncanonical Amino Acids in Synthetic Biology
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Genetic Code Expansion Approaches to Decipher the Ubiquitin Code
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Semi-enzymatic acceleration of oxidative protein folding by N -methylated heteroaromatic thiols
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“Switch points impact on the overall conformation and function of a August 2021 | Volume 11 | Article 637836 protein through conformational disturbances (Rehn et al., 2020).”
BackgroundEnzymatic and synthetic regulation of polypeptide folding
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C-terminal domain dimerization in yeast Hsp90 is moderately modulated by the other domains
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Impact of Co-chaperones and Posttranslational Modifications Toward Hsp90 Drug Sensitivity
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Second international symposium on the chaperone code, 2023
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The role of Aha1 in cancer and neurodegeneration
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Ligand‐driven modulation of chaperone–cochaperone networks shapes proteostasis outcomes
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“Another important modification of key residues is the methylation of the conserved K594 of yeast yHsp90 (K615 in human Hsp90 ɑ ) (Rehn et al., 2020), which is known to alter ATP hydrolysis, p23 binding and GR client regulation.”
A novel Hsp90 phospho-switch modulates virulence in the major human fungal pathogen Candida albicansPreprint
Alaalm, L., Crunden, J. L., Butcher, M. C., Obst, U., Whealy, R. N., Williamson, C. E., O’Brien, H., Schaffitzel, C., Ramage, G., & Diezmann, S. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.09.23.309831 · Cited by 2 · see citing works
HSP90.6 is involved in grain filling via carbon and nitrogen metabolism in maizePreprint
Xu, J., Yang, Z., Fei, X., Zhang, M., Cui, Y., Zhang, X., Tan, K., Lizhu, E., Zhao, H., Lai, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.27.489727 · Cited by 2 · see citing works
A modular genetic code expansion approach to site-specific lysine acylations
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- Authors
- Rehn, A., Lawatscheck, J., Jokisch, M.-L., Mader, S. L., Luo, Q., Tippel, F., Blank, B., Richter, K., Lang, K., Kaila, V. R. I., & Buchner, J.
- Affiliations
- Institut für Mikrobiologie der Bundeswehr (DE)
- Technical University of Munich (DE)
- NanoTemper Technologies (Germany) (DE)
- Max Planck Institute of Biochemistry (DE)
- Stockholm University (SE)
- ORCID
- Venue
- Nature Communications
- Published
- 2020-03-05
- Volume
- 11
- Issue
- 1
- Pages
- 1219-1219
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7057950
- OpenAlex
- W3010028259
- Cited by
- 38
- References
- 98
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 12 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 5
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-07-21)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (SFB1035 B10, SFB 1035 TP A03)
- 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, lysine methylation, C-terminal domain, conformational cycle, allosteric regulation, ATPase activity, genetic code expansion, molecular dynamics simulation
- MeSH terms
- Adenosine Triphosphate, Amino Acid Sequence, Lysine, Methylation, Mutation, Nucleotides, Saccharomyces cerevisiae, Structure-Activity Relationship, Conserved Sequence, HSP90 Heat-Shock Proteins, Molecular Dynamics Simulation
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