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

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

SUBMITTER: Goretzki B 

PROVIDER: S-EPMC10344929 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature