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Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity

Author

Listed:
  • Benedikt Goretzki

    (Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry
    Goethe University)

  • Christoph Wiedemann

    (Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry)

  • Brett A. McCray

    (Johns Hopkins University School of Medicine)

  • Stefan L. Schäfer

    (Max Planck Institute of Biophysics)

  • Jasmin Jansen

    (University of Konstanz
    University of Konstanz)

  • Frederike Tebbe

    (Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry)

  • Sarah-Ana Mitrovic

    (Johannes Gutenberg-University Mainz)

  • Julia Nöth

    (Johannes Gutenberg-University Mainz)

  • Ainara Claveras Cabezudo

    (Max Planck Institute of Biophysics
    IMPRS on Cellular Biophysics)

  • Jack K. Donohue

    (Johns Hopkins University School of Medicine)

  • Cy M. Jeffries

    (EMBL Hamburg Unit, Deutsches Elektronen-Synchrotron)

  • Wieland Steinchen

    (Philipps-University Marburg)

  • Florian Stengel

    (University of Konstanz
    University of Konstanz)

  • Charlotte J. Sumner

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Gerhard Hummer

    (Max Planck Institute of Biophysics
    Goethe University Frankfurt)

  • Ute A. Hellmich

    (Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry
    Goethe University
    Friedrich Schiller University Jena)

Abstract

Intrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. TRPV4, a member of the TRP vanilloid channel family involved in thermo- and osmosensation, has a large N-terminal IDR of approximately 150 amino acids. With an integrated structural biology approach, we analyze the structural ensemble of the TRPV4 IDR and the network of antagonistic regulatory elements it encodes. These modulate channel activity in a hierarchical lipid-dependent manner through transient long-range interactions. A highly conserved autoinhibitory patch acts as a master regulator by competing with PIP2 binding to attenuate channel activity. Molecular dynamics simulations show that loss of the interaction between the PIP2-binding site and the membrane reduces the force exerted by the IDR on the structured core of TRPV4. This work demonstrates that IDR structural dynamics are coupled to TRPV4 activity and highlights the importance of IDRs for TRP channel function and regulation.

Suggested Citation

  • Benedikt Goretzki & Christoph Wiedemann & Brett A. McCray & Stefan L. Schäfer & Jasmin Jansen & Frederike Tebbe & Sarah-Ana Mitrovic & Julia Nöth & Ainara Claveras Cabezudo & Jack K. Donohue & Cy M. J, 2023. "Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39808-4
    DOI: 10.1038/s41467-023-39808-4
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    References listed on IDEAS

    as
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    Cited by:

    1. Jingying Zhang & Grigory Maksaev & Peng Yuan, 2023. "Open structure and gating of the Arabidopsis mechanosensitive ion channel MSL10," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    2. F. Emil Thomasen & Tórur Skaalum & Ashutosh Kumar & Sriraksha Srinivasan & Stefano Vanni & Kresten Lindorff-Larsen, 2024. "Rescaling protein-protein interactions improves Martini 3 for flexible proteins in solution," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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