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Structure of human TRPV4 in complex with GTPase RhoA

Author

Listed:
  • Kirill D. Nadezhdin

    (Columbia University)

  • Irina A. Talyzina

    (Columbia University
    Columbia University)

  • Aravind Parthasarathy

    (Cardiovascular Center, Medical College of Wisconsin)

  • Arthur Neuberger

    (Columbia University)

  • David X. Zhang

    (Cardiovascular Center, Medical College of Wisconsin
    Medical College of Wisconsin)

  • Alexander I. Sobolevsky

    (Columbia University)

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.

Suggested Citation

  • Kirill D. Nadezhdin & Irina A. Talyzina & Aravind Parthasarathy & Arthur Neuberger & David X. Zhang & Alexander I. Sobolevsky, 2023. "Structure of human TRPV4 in complex with GTPase RhoA," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39346-z
    DOI: 10.1038/s41467-023-39346-z
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    References listed on IDEAS

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    1. Jonathan Mount & Grigory Maksaev & Brock T. Summers & James A. J. Fitzpatrick & Peng Yuan, 2022. "Structural basis for mechanotransduction in a potassium-dependent mechanosensitive ion channel," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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    4. Kirill D. Nadezhdin & Arthur Neuberger & Yury A. Nikolaev & Lyle A. Murphy & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2021. "Extracellular cap domain is an essential component of the TRPV1 gating mechanism," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
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    7. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2021. "Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    8. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2022. "Structural mechanism of TRPV3 channel inhibition by the anesthetic dyclonine," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
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    2. Melati S. Abdul Halim & Jennifer M. Dyson & Max M. Gong & Moira K. O’Bryan & Reza Nosrati, 2024. "Fallopian tube rheology regulates epithelial cell differentiation and function to enhance cilia formation and coordination," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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