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Structure of human TRPV4 in complex with GTPase RhoA. Nat Commun 2023 Jun 23;14(1):3733

Date

06/24/2023

Pubmed ID

37353478

Pubmed Central ID

PMC10290124

DOI

10.1038/s41467-023-39346-z

Scopus ID

2-s2.0-85162777271 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

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 4α-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 π-to-α 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.

Author List

Nadezhdin KD, Talyzina IA, Parthasarathy A, Neuberger A, Zhang DX, Sobolevsky AI

Authors

Aravind Parthasarathy Postdoctoral Fellow in the Medicine department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Ankyrin Repeat
Humans
TRPV Cation Channels
rhoA GTP-Binding Protein