CANUL-TEC, Juan; KUMAR, Anand; DHENIN, Jonathan; ASSAL, Redda; LEGRAND, Pierre; REY, Martial; CHAMOT-ROOKE, Julia; REYES, Nicolas

doi:10.15252/embj.2021108341

CANUL-TEC, Juan
Microbiologie Fondamentale et Pathogénicité [MFP]

KUMAR, Anand

Microbiologie Fondamentale et Pathogénicité [MFP]

DHENIN, Jonathan

Idioma

Article de revue

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EMBO Journal. 2022-01-04, vol. 41, n° 1, p. 377-390

EMBO Press

Resumen en inglés

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.< Leer menos

Palabras clave en inglés

cryo-EM

neurotransmitter transport

permeation and transport

solute carrier

X-ray crystallography

URI

https://oskar-bordeaux.fr/handle/20.500.12278/182127

DOI

http://dx.doi.org/10.15252/embj.2021108341

Proyecto europeo

Molecular bases of human excitatory neurotransmitter transport across the plasma membrane

Proyecto ANR

Centre d'analyse de systèmes complexes dans les environnements complexes - ANR-11-EQPX-0008

Centros de investigación

MFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234

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The ion‐coupling mechanism of human excitatory amino acid transporters