The ion‐coupling mechanism of human excitatory amino acid transporters
CHAMOT-ROOKE, Julia
Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology [UTechS MSBio]
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Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology [UTechS MSBio]
Language
en
Article de revue
This item was published in
EMBO Journal. 2022-01-04, vol. 41, n° 1, p. 377-390
EMBO Press
English 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 ...Read more >
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.Read less <
English Keywords
cryo-EM
neurotransmitter transport
permeation and transport
solute carrier
X-ray crystallography
European Project
Molecular bases of human excitatory neurotransmitter transport across the plasma membrane
ANR Project
Centre d'analyse de systèmes complexes dans les environnements complexes - ANR-11-EQPX-0008