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

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2023

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Goretzki, Benedikt
Wiedemann, Christoph
McCray, Brett A.
Schäfer, Stefan L.
Tebbe, Frederike
Mitrovic, Sarah-Ana
Nöth, Julia
Hellmich, Ute A.
et al.

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Nature Communications. Springer. 2023, 14(1), 4165. eISSN 2041-1723. Verfügbar unter: doi: 10.1038/s41467-023-39808-4

Zusammenfassung

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.

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570 Biowissenschaften, Biologie

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ISO 690GORETZKI, Benedikt, Christoph WIEDEMANN, Brett A. MCCRAY, Stefan L. SCHÄFER, Jasmin JANSEN, Frederike TEBBE, Sarah-Ana MITROVIC, Julia NÖTH, Florian STENGEL, Ute A. HELLMICH, 2023. Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity. In: Nature Communications. Springer. 2023, 14(1), 4165. eISSN 2041-1723. Verfügbar unter: doi: 10.1038/s41467-023-39808-4
BibTex
@article{Goretzki2023-07-13Cross-71233,
  year={2023},
  doi={10.1038/s41467-023-39808-4},
  title={Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity},
  number={1},
  volume={14},
  journal={Nature Communications},
  author={Goretzki, Benedikt and Wiedemann, Christoph and McCray, Brett A. and Schäfer, Stefan L. and Jansen, Jasmin and Tebbe, Frederike and Mitrovic, Sarah-Ana and Nöth, Julia and Stengel, Florian and Hellmich, Ute A.},
  note={Article Number: 4165}
}
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