Bestrophin-2 and glutamine synthetase form a complex for glutamate release

• Type of Material: Article
• Authors: Aaron P Owji, Columbia University; Kuai Yu, Emory University; Alec Kittredge, Columbia University; Jiali Wang, Columbia University; Yu Zhang, Columbia University; Tingting Yang, Columbia University
• Language: English
• Date: 2022-10-26
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, The Author(s), under exclusive licence to Springer Nature Limited
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-022-05373-x
• Title of Journal or Parent Work: NATURE
• Volume: 611
• Issue: 7934
• Start Page: 180
• End Page: +
• Keywords: GLAUCOMA; CRYO-EM; Science & Technology - Other Topics; TOOLS; REFINEMENT; ASTROCYTES; Science & Technology; VALIDATION; CHANNEL; MODEL; LOCALIZATION; Multidisciplinary Sciences; BEAM-INDUCED MOTION

Abstract

Bestrophin-2 (BEST2) is a member of the bestrophin family of calcium-activated anion channels that has a critical role in ocular physiology1–4. Here we uncover a directional permeability of BEST2 to glutamate that heavily favours glutamate exit, identify glutamine synthetase (GS) as a binding partner of BEST2 in the ciliary body of the eye, and solve the structure of the BEST2–GS complex. BEST2 reduces cytosolic GS activity by tethering GS to the cell membrane. GS extends the ion conducting pathway of BEST2 through its central cavity and inhibits BEST2 channel function in the absence of intracellular glutamate, but sensitizes BEST2 to intracellular glutamate, which promotes the opening of BEST2 and thus relieves the inhibitory effect of GS. We demonstrate the physiological role of BEST2 in conducting chloride and glutamate and the influence of GS in non-pigmented ciliary epithelial cells. Together, our results reveal a novel mechanism of glutamate release through BEST2–GS.