Cited by 38Heat shock proteins researchProtein Structure and DynamicsUbiquitin and proteasome pathways

A methylated lysine is a switch point for conformational communication in the chaperone Hsp90

Open access
Rehn, Alexandra, Lawatscheck, Jannis, Jokisch, Marie-Lena, Mader, Sophie L., Luo, Qi, Tippel, Franziska, Blank, Birgit, Richter, Klaus +3 more·2020·Nature Communications

Abstract

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).”

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Research works printed but not linked: 1

  1. [88]Mayer SV Murnauer A von Wrisberg MK Jokisch ML Lang K Photo-induced and rapid labeling of tetrazine-bearing proteins via cyclopropenone-caged bicyclononynes Angew. Chem. Int. Ed. Engl. 2019 58 15876 15882 10.1002/anie.201908209 31476269 PMC6856800 · DOI

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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)
Venue
Nature Communications
Published
2020-03-05
Volume
11
Issue
1
Pages
1219-1219
ISSN
2041-1723 (ISSN-L)
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
Open access
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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