Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05616-4
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Funding
- New York Structural Biology Center (Center on Membrane Protein Production and Analysis) [GM116799]
- Sun Yat-Sen University 100 Top Talents Program (II), Special fund for scientific and technological innovation strategy of Guangdong Province of China [2017A030313145]
- National Natural Science Foundation of China [31770801]
- NIH [EY025290, GM127652]
- University of Rochester
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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 patients-pecific mutation.
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