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

• Published in: Nature communications Vol. 14; no. 1; pp. 4165 - 20
• Main Authors: Goretzki, Benedikt, Wiedemann, Christoph, McCray, Brett A., Schäfer, Stefan L., Jansen, Jasmin, Tebbe, Frederike, Mitrovic, Sarah-Ana, Nöth, Julia, Cabezudo, Ainara Claveras, Donohue, Jack K., Jeffries, Cy M., Steinchen, Wieland, Stengel, Florian, Sumner, Charlotte J., Hummer, Gerhard, Hellmich, Ute A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-07-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 140/58; 631/45/269/1153; 631/57; 82/6; 82/80; 82/83; Amino acids; Binding sites; Biology; Cell Physiological Phenomena; Channel gating; Crosstalk; Humanities and Social Sciences; Ion channels; Lipids; Membranes; Molecular dynamics; multidisciplinary; N-Terminus; Phosphatidylinositol 4,5-diphosphate; Protein Domains; Regulatory sequences; Regulatory Sequences, Nucleic Acid; Science; Science (multidisciplinary); TRPV Cation Channels - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39808-4

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 PIP
2
binding to attenuate channel activity. Molecular dynamics simulations show that loss of the interaction between the PIP
2
-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.
An integrated structural biology approach uncovers the structural complexity of the intrinsically disordered region (IDR) within the TRPV4 ion channel. Multiple stimulatory and inhibitory elements were identified within the IDR that modulate channel activity in a lipid-dependent manner.