Dual Ca2+-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations

Autor:	Tingting Yang, Nancy Ward, Alec Kittredge, Shoudeng Chen, Yu Zhang, Changyi Ji, Yohta Fukuda, Austin Hopiavuori
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	Patch-Clamp Techniques Conducting pathway Biophysics Medicine (miscellaneous) Gating Article General Biochemistry Genetics and Molecular Biology Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Chloride Channels Humans Patch clamp Bestrophins lcsh:QH301-705.5 X-ray crystallography 030304 developmental biology Physics 0303 health sciences Crystallography Channel gating Hereditary eye disease 3. Good health Cell biology HEK293 Cells Gain of function Membrane protein lcsh:Biology (General) Gain of Function Mutation Chloride channel Permeation and transport Calcium General Agricultural and Biological Sciences Ion Channel Gating 030217 neurology & neurosurgery
Zdroj:	Communications Biology, Vol 2, Iss 1, Pp 1-13 (2019) Communications Biology
ISSN:	2399-3642
DOI:	10.1038/s42003-019-0433-3
Popis:	Mutations of human BEST1, encoding a Ca2+-activated Cl− channel (hBest1), cause macular degenerative disorders. Best1 homolog structures reveal an evolutionarily conserved channel architecture highlighted by two landmark restrictions (named the “neck” and “aperture”, respectively) in the ion conducting pathway, suggesting a unique dual-switch gating mechanism, which, however, has not been characterized well. Using patch clamp and crystallography, we demonstrate that both the neck and aperture in hBest1 are Ca2+-dependent gates essential for preventing channel leakage resulting from Ca2+-independent, spontaneous gate opening. Importantly, three patient-derived mutations (D203A, I205T and Y236C) lead to Ca2+-independent leakage and elevated Ca2+-dependent anion currents due to enhanced opening of the gates. Moreover, we identify a network of residues critically involved in gate operation. Together, our results suggest an indispensable role of the neck and aperture of hBest1 for channel gating, and uncover disease-causing mechanisms of hBest1 gain-of-function mutations. Ji and Kittredge et al. demonstrate that the neck and aperture of human Bestrophin1, a Ca2+-activated Cl- channel, are both Ca2+-dependent gates. By showing hyper-activity of Bestrophin1, which is associated with its enhanced gate opening in the presence of three patient-derived mutations, this study provides mechanistic insights into the gain-of-function mutations that cause macular degenerative disease.
Databáze:	OpenAIRE
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