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

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. Jeffries, Wieland Steinchen, Florian Stengel, Charlotte J. Sumner, Gerhard Hummer and Ute A. Hellmich ()
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Benedikt Goretzki: Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry
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
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
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
Charlotte J. Sumner: Johns Hopkins University School of Medicine
Gerhard Hummer: Max Planck Institute of Biophysics
Ute A. Hellmich: Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39808-4

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