Hierarchical antagonistic regulatory elements in the TRPV4 intrinsically disordered N-terminus modulate lipid binding and channel activity through transient long-range interactions

Intrinsically disordered regions (IDRs) are important for the functional regulation of membrane receptors. Among the TRP Vanilloid channels involved in thermo- and osmosensation, TRPV4 features the largest N-terminal IDR of ~150 residues. Here, we elucidate the structural ensemble of the TRPV4 IDR through an integrated structural biology approach. Novel structural and functional properties can be assigned to distinct IDR regions. Along the length of the entire IDR, a hierarchical interaction network of structurally and functionally coupled antagonistic regulatory modules can be mapped. Long-range transient crosstalk between these regulatory elements mediates channel responses to osmotic stimuli. Most notably, a highly conserved regulatory patch in the N-terminal IDR asserts dominant negative control over lipid binding and channel activity by acting on a sensitizing PIP2 binding site in the C-terminal IDR. This work demonstrates the importance of IDRs and “IDR cartography” for understanding TRP channel function and regulation.