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ATP activates bestrophin ion channels through direct interaction

Author

Listed:
  • Yu Zhang

    (University of Rochester, School of Medicine and Dentistry)

  • Alec Kittredge

    (University of Rochester, School of Medicine and Dentistry)

  • Nancy Ward

    (University of Rochester, School of Medicine and Dentistry)

  • Changyi Ji

    (University of Rochester, School of Medicine and Dentistry)

  • Shoudeng Chen

    (The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai)

  • Tingting Yang

    (University of Rochester, School of Medicine and Dentistry)

Abstract

Human Bestrophin1 (hBest1) is a Ca2+-activated Cl− channel in retinal pigment epithelium (RPE) essential for retina physiology, and its mutation results in retinal degenerative diseases that have no available treatments. Here, we discover that hBest1’s channel activity in human RPE is significantly enhanced by adenosine triphosphate (ATP) in a dose-dependent manner. We further demonstrate a direct interaction between ATP and bestrophins, and map the ATP-binding motif on hBest1 to an intracellular loop adjacent to the channel activation gate. Importantly, a disease-causing mutation of hBest1 located within the ATP-binding motif, p.I201T, diminishes ATP-dependent activation of the channel in patient-derived RPE, while the corresponding mutants in bestrophin homologs display defective ATP binding and a conformational change in the ATP-binding motif. Taken together, our results identify ATP as a critical activator of bestrophins, and reveal the molecular mechanism of an hBest1 patient-specific mutation.

Suggested Citation

  • Yu Zhang & Alec Kittredge & Nancy Ward & Changyi Ji & Shoudeng Chen & Tingting Yang, 2018. "ATP activates bestrophin ion channels through direct interaction," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05616-4
    DOI: 10.1038/s41467-018-05616-4
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    Cited by:

    1. Aaron P. Owji & Jiali Wang & Alec Kittredge & Zada Clark & Yu Zhang & Wayne A. Hendrickson & Tingting Yang, 2022. "Structures and gating mechanisms of human bestrophin anion channels," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Jiali Wang & Aaron P. Owji & Alec Kittredge & Zada Clark & Yu Zhang & Tingting Yang, 2024. "GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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