9CTT

Best1 + GABA closed state

Summary for 9CTT

• Entry DOI: 10.2210/pdb9ctt/pdb
• EMDB information: 45918
• Descriptor: Bestrophin-1, CALCIUM ION (2 entities in total)
• Functional Keywords: calcium-activated chloride channel, gaba type a receptor, gaba-bound anion channel, channel-activator complex, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 338346.76

Authors

Owji, A.P.,Kittredge, A.,Zhang, Y.,Yang, T. (deposition date: 2024-07-25, release date: 2024-09-25)

Primary citation

Wang, J.,Owji, A.P.,Kittredge, A.,Clark, Z.,Zhang, Y.,Yang, T.
GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel.
Nat Commun, 15:8051-8051, 2024

PubMed Abstract: Bestrophin-1 (Best1) is an anion channel genetically linked to vision-threatening retinal degenerative channelopathies. Here, we identify interactions between Best1 and both isoforms of glutamic acid decarboxylases (GAD65 and GAD67), elucidate the distinctive influences of GAD65 and GAD67 on Best1's permeability to various anions/neurotransmitters, discover the functionality of Best1 as a γ-Aminobutyric acid (GABA) type A receptor, and solve the structure of GABA-bound Best1. GAD65 and GAD67 both promote Best1-mediated Cl currents, but only GAD65 drastically enhances the permeability of Best1 to glutamate and GABA, for which GAD67 has no effect. GABA binds to Best1 on an extracellular site and stimulates Best1-mediated Cl currents at the nano-molar concentration level. The physiological role of GAD65 as a cell type-specific binding partner and facilitator of Best1 is demonstrated in retinal pigment epithelial cells. Together, our results reveal critical regulators of Best1 and inform a network of membrane transport metabolons formed between bestrophin channels and glutamate metabolic enzymes.

PubMed: 39277606
DOI: 10.1038/s41467-024-52039-5

Experimental method

ELECTRON MICROSCOPY (2.5 Å)