The ion-coupling mechanism of human excitatory amino acid transporters.
EMBO J
; 41(1): e108341, 2022 01 04.
Article
en En
| MEDLINE
| ID: mdl-34747040
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transportador 1 de Aminoácidos Excitadores
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
EMBO J
Año:
2022
Tipo del documento:
Article
País de afiliación:
Francia