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

  • 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 identify a network of regulatory elements that 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.

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar
Author:Benedikt GoretzkiORCiDGND, Christoph WiedemannORCiDGND, Brett A. McCrayORCiD, Stefan L. SchäferORCiD, Jasmin JansenORCiD, Frederike TebbeORCiD, Sarah-Ana Mitrovic, Julia NöthORCiD, Jack K. DonohueORCiD, Cy M. JeffriesORCiD, Wieland SteinchenORCiD, Florian StengelORCiD, Charlotte J. SumnerORCiDGND, Gerhard HummerORCiD, Ute HellmichORCiDGND
Parent Title (English):bioRxiv
Document Type:Preprint
Date of Publication (online):2022/12/22
Date of first Publication:2022/12/22
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/04/19
Page Number:37
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - CC BY-NC - Namensnennung - Nicht kommerziell 4.0 International