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-Structure paper
タイトル | The ion-coupling mechanism of human excitatory amino acid transporters. |
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ジャーナル・号・ページ | EMBO J, Vol. 41, Issue 1, Page e108341, Year 2022 |
掲載日 | 2022年1月4日 |
著者 | Juan C Canul-Tec / Anand Kumar / Jonathan Dhenin / Reda Assal / Pierre Legrand / Martial Rey / Julia Chamot-Rooke / Nicolas Reyes / |
PubMed 要旨 | Excitatory amino acid transporters (EAATs) maintain glutamate gradients in the brain essential for neurotransmission and to prevent neuronal death. They use ionic gradients as energy source and co- ...Excitatory amino acid transporters (EAATs) maintain glutamate gradients in the brain essential for neurotransmission and to prevent neuronal death. They use ionic gradients as energy source and co-transport transmitter into the cytoplasm with Na and H , while counter-transporting K to re-initiate the transport cycle. However, the molecular mechanisms underlying ion-coupled transport remain incompletely understood. Here, we present 3D X-ray crystallographic and cryo-EM structures, as well as thermodynamic analysis of human EAAT1 in different ion bound conformations, including elusive counter-transport ion bound states. Binding energies of Na and H , and unexpectedly Ca , are coupled to neurotransmitter binding. Ca competes for a conserved Na site, suggesting a regulatory role for Ca in glutamate transport at the synapse, while H binds to a conserved glutamate residue stabilizing substrate occlusion. The counter-transported ion binding site overlaps with that of glutamate, revealing the K -based mechanism to exclude the transmitter during the transport cycle and to prevent its neurotoxic release on the extracellular side. |
リンク | EMBO J / PubMed:34747040 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 3.25 - 3.99 Å |
構造データ | EMDB-12524, PDB-7npw: PDB-7awl: PDB-7awm: PDB-7awn: PDB-7awp: PDB-7awq: |
化合物 | ChemComp-6Z6: ChemComp-BA: ChemComp-NA: ChemComp-ASP: ChemComp-RB: |
由来 |
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キーワード | MEMBRANE PROTEIN / excitatory amino acid transporter 1 / human glutamate transporter / SLC1A3 / ion-coupling mechanism / allosteric inhibitor UCPH101 / TRANSPORT PROTEIN / Human Membrane Protein / Transporter / Glutamate transporter |