9kca
Cryo-EM structure of docked mouse bestrophin-1 in a closed state
Structural highlights
FunctionC562_ECOLX Electron-transport protein of unknown function.BEST1_MOUSE Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+) (By similarity). Allows the movement of chloride and hydrogencarbonate (By similarity). Found in a partially open conformation leading to significantly smaller chloride movement (By similarity). Upon F2R/PAR-1 activation, the sequestered calcium is released into the cytosol of astrocytes, leading to the (Ca2+)-dependent release of L-glutamate into the synaptic cleft that targets the neuronal postsynaptic GRIN2A/NMDAR receptor resulting in the synaptic plasticity regulation (PubMed:23021213, PubMed:25645137, PubMed:29121962). Upon activation of the norepinephrine-alpha-1 adrenergic receptor signaling pathway, transports as well D-serine than L-glutamate in a (Ca2+)-dependent manner, leading to activation of adjacent NMDAR receptors and therefore regulates the heterosynaptic long-term depression and metaplasticity during initial memory acquisition (PubMed:34952697). Releases the 4-aminobutanoate neurotransmitter in a (Ca2+)-dependent manner, and participates in its tonic release from cerebellar glial cells (PubMed:20929730).[UniProtKB:O76090][1] [2] [3] [4] [5] Publication Abstract from PubMedBestrophin 1 (BEST1) channels are calcium-activated Cl(-) channels involved in diverse physiological processes, including gliotransmitter release in astrocytes. Although human and chicken BEST1 orthologs have been extensively studied, the structural and functional properties of mouse BEST1 (mBEST1) remain poorly understood. In this study, we characterized the structure-function of mBEST1-BF, a C-terminally tagged variant, using whole-cell patch-clamp recordings, surface biotinylation assays, and single-particle cryo-electron microscopy. Cryo-electron microscopy structural analysis of mBEST1-BF revealed closed and partially open conformations. Comparative analysis with human and chicken BEST1 orthologs highlighted conserved calcium-binding and gating mechanisms, with distinct features in mBEST1, including a wider aperture sufficient to accommodate dehydrated Cl(-) ions and potential anion-binding sites near Val205 and Gln208 residues. The disordered C-terminal region of mBEST1 remains unresolved, suggesting it may require stabilizing factors for structural determination. Additionally, the autoinhibitory domain, which includes Ser354, likely plays a key role in regulating gating, with Ser354 potentially serving as a phosphorylation site that modulates channel activity. Our findings provide structural and functional insights into mBEST1 and suggest mechanisms underlying its unique gating and ion permeation properties. Cryo-EM structures of mouse bestrophin 1 channel in closed and partially open conformations.,Kim KW, Lee E, Ko A, Hwang J, Park K, Lee BC, Kim KW, Oh WJ, Kim K, Lim HH Mol Cells. 2025 Mar 3;48(5):100208. doi: 10.1016/j.mocell.2025.100208. PMID:40043778[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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