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

Ji, Changyi; Kittredge, Alec; Hopiavuori, Austin; Ward, Nancy; Chen, Shoudeng; Fukuda, Yohta; Zhang, Yu; Yang, Tingting

doi:10.1038/s42003-019-0433-3

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

Journal Article · Mon Jun 24 00:00:00 EDT 2019 · Communications Biology

DOI:https://doi.org/10.1038/s42003-019-0433-3· OSTI ID:1579961

Ji, Changyi ^[1]; Kittredge, Alec ^[1]; Hopiavuori, Austin ^[1]; Ward, Nancy ^[1]; Chen, Shoudeng ^[2]; Fukuda, Yohta ^[3]; Zhang, Yu ^[1]; Yang, Tingting ^[1]

Univ. of Rochester, NY (United States)
Sun Yat-Sen Univ., Guangzhou (China)
Osaka Univ. (Japan)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Natural Science Foundation of China (NSFC); Japan Society for the Promotion of Science (JSPS); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; 2017A030313145; 2018B030306029; 317708801; 17K17862; EY025290; GM127652

OSTI ID:: 1579961

Journal Information:: Communications Biology, Vol. 2, Issue 1; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 11 works

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

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