Structure of human TRPV4 in complex with GTPase RhoA

Nadezhdin et al. present structures of human TRPV4 in complex with the GTPase RhoA, in the apo, agonist 4 & alpha;-PDD and antagonist HC-067047 bound states, uncovering the mechanisms of channel activation, inhibition and disease-causing mutations. Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4 & alpha;-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a & pi;-to-& alpha; transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases.

Automated summary

Nadezhdin et al. present structures of human TRPV4 in complex with the GTPase RhoA, revealing the mechanisms of channel activation, inhibition, and disease-causing mutations. TRPV4 is a polymodal cellular sensor involved in various physiological processes and diseases. The study demonstrates the interaction between TRPV4 and RhoA, identifies the binding sites of agonist 4α-PDD and inhibitor HC-067047, and provides insights into the activation and inhibition of TRPV4, laying the foundation for the development of therapeutics for TRPV4-related diseases.