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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Zhang Y,Kittredge A,Ward N,Ji C,Chen S,Yang Tdoi
10.1038/s41467-018-05616-4subject
Has Abstractpub_date
2018-08-07 00:00:00pages
3126issue
1issn
2041-1723pii
10.1038/s41467-018-05616-4journal_volume
9pub_type
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