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The ion‐coupling mechanism of human excitatory amino acid transporters

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-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 Ca2+, are coupled to neurotransmitter binding. Ca2+ competes for a conserved Na+ site, suggesting a regulatory role for Ca2+ 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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https://hal-pasteur.archives-ouvertes.fr/pasteur-03795591
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Submitted on : Friday, October 7, 2022 - 1:11:36 PM
Last modification on : Friday, October 7, 2022 - 3:31:03 PM

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Juan C Canul-Tec, Anand Kumar, Jonathan Dhenin, Redda Assal, Pierre Legrand, et al.. The ion‐coupling mechanism of human excitatory amino acid transporters. EMBO Journal, 2022, 41 (1), pp.377-390. ⟨10.15252/embj.2021108341⟩. ⟨pasteur-03795591⟩

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