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Title | The ion-coupling mechanism of human excitatory amino acid transporters. |
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Journal, issue, pages | EMBO J, Vol. 41, Issue 1, Page e108341, Year 2022 |
Publish date | Jan 4, 2022 |
![]() | Juan C Canul-Tec / Anand Kumar / Jonathan Dhenin / Reda Assal / Pierre Legrand / Martial Rey / Julia Chamot-Rooke / Nicolas Reyes / ![]() |
PubMed Abstract | 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. |
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Methods | EM (single particle) / X-ray diffraction |
Resolution | 3.25 - 3.99 Å |
Structure data | EMDB-12524, PDB-7npw: ![]() PDB-7awl: ![]() PDB-7awm: ![]() PDB-7awn: ![]() PDB-7awp: ![]() PDB-7awq: |
Chemicals | ![]() ChemComp-6Z6: ![]() ChemComp-BA: ![]() ChemComp-NA: ![]() ChemComp-ASP: ![]() ChemComp-RB: |
Source |
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![]() | 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 |