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TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease

Author

Listed:
  • Do Hoon Kwon

    (Duke University School of Medicine)

  • Feng Zhang

    (Duke University School of Medicine)

  • Brett A. McCray

    (Johns Hopkins University School of Medicine)

  • Shasha Feng

    (Lehigh University)

  • Meha Kumar

    (Johns Hopkins University School of Medicine)

  • Jeremy M. Sullivan

    (Johns Hopkins University School of Medicine)

  • Wonpil Im

    (Lehigh University)

  • Charlotte J. Sumner

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Seok-Yong Lee

    (Duke University School of Medicine)

Abstract

Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the ligand-free, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that RhoA serves as an auxiliary subunit for TRPV4, regulating TRPV4-mediated calcium homeostasis and disruption of TRPV4-RhoA interactions can lead to TRPV4-related neuromuscular disease. These insights will help facilitate TRPV4 therapeutics development.

Suggested Citation

  • Do Hoon Kwon & Feng Zhang & Brett A. McCray & Shasha Feng & Meha Kumar & Jeremy M. Sullivan & Wonpil Im & Charlotte J. Sumner & Seok-Yong Lee, 2023. "TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39345-0
    DOI: 10.1038/s41467-023-39345-0
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    1. Peter Eastman & Jason Swails & John D Chodera & Robert T McGibbon & Yutong Zhao & Kyle A Beauchamp & Lee-Ping Wang & Andrew C Simmonett & Matthew P Harrigan & Chaya D Stern & Rafal P Wiewiora & Bernar, 2017. "OpenMM 7: Rapid development of high performance algorithms for molecular dynamics," PLOS Computational Biology, Public Library of Science, vol. 13(7), pages 1-17, July.
    2. Do Hoon Kwon & Feng Zhang & Justin G. Fedor & Yang Suo & Seok-Yong Lee, 2022. "Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Brett A. McCray & Erika Diehl & Jeremy M. Sullivan & William H. Aisenberg & Nicholas W. Zaccor & Alexander R. Lau & Dominick J. Rich & Benedikt Goretzki & Ute A. Hellmich & Thomas E. Lloyd & Charlotte, 2021. "Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Hiroyuki Watanabe & Joris Vriens & Jean Prenen & Guy Droogmans & Thomas Voets & Bernd Nilius, 2003. "Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels," Nature, Nature, vol. 424(6947), pages 434-438, July.
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    Cited by:

    1. Benedikt Goretzki & Christoph Wiedemann & Brett A. McCray & Stefan L. Schäfer & Jasmin Jansen & Frederike Tebbe & Sarah-Ana Mitrovic & Julia Nöth & Ainara Claveras Cabezudo & Jack K. Donohue & Cy M. J, 2023. "Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Yuan Lin & Theresa A. Ramelot & Simge Senyuz & Attila Gursoy & Hyunbum Jang & Ruth Nussinov & Ozlem Keskin & Yi Zheng, 2024. "Tumor-derived RHOA mutants interact with effectors in the GDP-bound state," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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