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Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A

Author

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  • Bo-Hyun Lee

    (Rutgers, New Jersey Medical School
    Gyeongsang National University Medical School)

  • José J. Jesús Pérez

    (University of Pennsylvania)

  • Vera Moiseenkova-Bell

    (University of Pennsylvania)

  • Tibor Rohacs

    (Rutgers, New Jersey Medical School)

Abstract

Long-chain acyl-coenzyme A (LC-CoA) is a crucial metabolic intermediate that plays important cellular regulatory roles, including activation and inhibition of ion channels. The structural basis of ion channel regulation by LC-CoA is not known. Transient receptor potential vanilloid 5 and 6 (TRPV5 and TRPV6) are epithelial calcium-selective ion channels. Here, we demonstrate that LC-CoA activates TRPV5 and TRPV6 in inside-out patches, and both exogenously supplied and endogenously produced LC-CoA can substitute for the natural ligand phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in maintaining channel activity in intact cells. Utilizing cryo-electron microscopy, we determined the structure of LC-CoA-bound TRPV5, revealing an open configuration with LC-CoA occupying the same binding site as PI(4,5)P2 in previous studies. This is consistent with our finding that PI(4,5)P2 could not further activate the channels in the presence of LC-CoA. Our data provide molecular insights into ion channel regulation by a metabolic signaling molecule.

Suggested Citation

  • Bo-Hyun Lee & José J. Jesús Pérez & Vera Moiseenkova-Bell & Tibor Rohacs, 2023. "Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41577-z
    DOI: 10.1038/s41467-023-41577-z
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    1. Asmundur Oddsson & Patrick Sulem & Hannes Helgason & Vidar O. Edvardsson & Gudmar Thorleifsson & Gardar Sveinbjörnsson & Eik Haraldsdottir & Gudmundur I. Eyjolfsson & Olof Sigurdardottir & Isleifur Ol, 2015. "Common and rare variants associated with kidney stones and biochemical traits," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
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    Cited by:

    1. Matthew Gabrielle & Yevgen Yudin & Yujue Wang & Xiaoyang Su & Tibor Rohacs, 2024. "Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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