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ATP plays a structural role in Hsp90 function

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  • Michael Reidy

    (National Institutes of Health)

  • Daniel C. Masison

    (National Institutes of Health)

Abstract

Hsp90 is a highly conserved ATP-dependent molecular chaperone that forms a clamp around client proteins. The role of ATP in Hsp90 function is unclear since cell viability requires ATP binding, but not hydrolysis. Here, we present findings that support our hypothesis that after ATP binds, the γ phosphate repositions in a regulated manner to interact with a conserved arginine (R380) and stabilize the closed clamp. We propose that the essential role of ATP in Hsp90 function is structural: ATP is a linker that physically tethers the N and M domains and stabilizes closing. Severing this link by hydrolysis facilitates reopening. Our findings support the idea that R380 is an arginine finger, a motif found in diverse NTPase families, due to its interdomain interaction with ATP. This in turn suggests that for some arginine fingers the nucleotide itself is a structural element important for stabilization of inter-domain or -subunit interactions.

Suggested Citation

  • Michael Reidy & Daniel C. Masison, 2025. "ATP plays a structural role in Hsp90 function," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61962-0
    DOI: 10.1038/s41467-025-61962-0
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    References listed on IDEAS

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    1. Stefan Riedl & Ecenaz Bilgen & Ganesh Agam & Viivi Hirvonen & Alexander Jussupow & Franziska Tippl & Maximilian Riedl & Andreas Maier & Christian F. W. Becker & Ville R. I. Kaila & Don C. Lamb & Johan, 2024. "Evolution of the conformational dynamics of the molecular chaperone Hsp90," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Michael Reidy & Kevin Garzillo & Daniel C. Masison, 2023. "Nucleotide exchange is sufficient for Hsp90 functions in vivo," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Sophie L. Mader & Abraham Lopez & Jannis Lawatscheck & Qi Luo & Daniel A. Rutz & Ana P. Gamiz-Hernandez & Michael Sattler & Johannes Buchner & Ville R. I. Kaila, 2020. "Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    4. Leonie Vollmar & Julia Schimpf & Bianca Hermann & Thorsten Hugel, 2024. "Cochaperones convey the energy of ATP hydrolysis for directional action of Hsp90," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. Jasmeen Oberoi & Xavi Aran Guiu & Emily A. Outwin & Pascale Schellenberger & Theodoros I. Roumeliotis & Jyoti S. Choudhary & Laurence H. Pearl, 2022. "HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Peter J. Watson & Christopher J. Millard & Andrew M. Riley & Naomi S. Robertson & Lyndsey C. Wright & Himali Y. Godage & Shaun M. Cowley & Andrew G. Jamieson & Barry V. L. Potter & John W. R. Schwabe, 2016. "Insights into the activation mechanism of class I HDAC complexes by inositol phosphates," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
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