ATP activates bestrophin ion channels through direct interaction.

Publication Type:

Journal Article

Authors:

Zhang, Yu; Kittredge, Alec; Ward, Nancy; Ji, Changyi; Chen, Shoudeng; Yang, Tingting

Source:

Nat Commun, Volume 9, Issue 1, p.3126 (2018)

Keywords:

Adenosine Triphosphate, Amino Acid Motifs, Animals, Bestrophins, Calcium, Chickens, Chlorides, Electrophysiological Phenomena, HEK293 Cells, Humans, Mice, Mutation, Protein Domains, Protein Structure, Secondary, Retinal Pigment Epithelium, Xenopus laevis

Abstract:

<p>Human Bestrophin1 (hBest1) is a Ca-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&#39;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.</p>