The transient receptor potential (TRP) ion channel superfamily of integral membrane proteins is enriched for intrinsically disordered regions (IDRs), which have typically been excluded or unresolved in structural and functional characterization efforts owing to their intractable nature. The N terminus of TRPV4, a channel in the TRP vanilloid subfamily associated with severe channelopathies, constitutes one of the largest TRP channel IDRs. Two regulatory motifs, a proline-rich region and a PIP2-binding site for the essential ion channel regulator, were previously identified in the N-terminal domain, but insights into the functional relevance of the entire IDR have been lacking. To shed light onto the functionality of the TRPV4 IDR, Goretzki et al. implemented an integrative structural biology approach to determine a structural ensemble of the complete TRPV4 channel IDR linked to channel activity. Combining small-angle X-ray scattering, nuclear magnetic resonance, tryptophan fluorescence spectroscopy, molecular dynamics simulations, cross-linking and H/D exchange mass spectrometry, as well as functional assays, they identified multiple stimulatory and inhibitory elements within the TRPV4 IDR that modulate channel activity in a lipid-dependent yet hierarchical manner. Notably, the master regulator of TRPV4 channel function is an autoinhibitory patch in the distal IDR N terminus that attenuates TRPV4’s activity by competing with the binding of PIP2 to a stimulatory site in the IDR C terminus. Molecular dynamics simulations showed that binding of the IDR to the membrane could transduce mechanical forces to the TRPV4 core. This work provides compelling mechanistic detail on the part played by the IDR to enhance or inhibit TRPV4’s activity in a lipid-dependent manner, and invigorates the examination of these neglected regions in the functional characterization of complex IDR-rich membrane receptors.
Original reference: Nat. Commun. 14, 4165 (2023)
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