ATP activates bestrophin ion channels through direct interaction

• Published in: Nature communications 2018-08, Vol.9 (1), p.3126-11, Article 3126
• Main Authors: Zhang, Yu, Kittredge, Alec, Ward, Nancy, Ji, Changyi, Chen, Shoudeng, Yang, Tingting
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/106; 13/109; 631/1647/1453/1970; 631/1647/1453/2207; 631/45/269/1147; 631/45/535; 631/532/2064/2158; 82/16; 82/80; 82/83; 9/74; 9/97; Activation; Adenosine triphosphate; Adenosine Triphosphate - metabolism; Amino Acid Motifs; Animals; ATP; Bestrophins - metabolism; Binding; Calcium; Calcium - metabolism; Calcium ions; Channel gating; Chickens; Chlorides - chemistry; Degenerative diseases; Electrophysiological Phenomena; Epithelium; HEK293 Cells; Homology; Humanities and Social Sciences; Humans; Ion channels; Mice; multidisciplinary; Mutation; Protein Domains; Protein Structure, Secondary; Retina; Retinal degeneration; Retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Science; Science (multidisciplinary); Xenopus laevis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05616-4

Human Bestrophin1 (hBest1) is a Ca 2+ -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. Human Bestrophin1 (hBest1), a calcium-activated chloride channel in retinal pigment epithelium (RPE), is essential for retina physiology. Using electrophysiological and structural approaches, the authors uncover an ATP-dependent activation mechanism of hBest1, and identify an ATP-binding motif.