7npw
From Proteopedia
Cryo-EM structure of Human excitatory amino acid transporters-1 (EAAT1) in potassium buffer
Structural highlights
Disease[EAA1_HUMAN] Alternating hemiplegia of childhood;Episodic ataxia type 6. The disease is caused by mutations affecting the gene represented in this entry. Function[EAA1_HUMAN] Transports L-glutamate and also L- and D-aspartate. Essential for terminating the postsynaptic action of glutamate by rapidly removing released glutamate from the synaptic cleft. Acts as a symport by cotransporting sodium. Publication Abstract from PubMedExcitatory 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(2+) , are coupled to neurotransmitter binding. Ca(2+) competes for a conserved Na(+) site, suggesting a regulatory role for Ca(2+) 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. The ion-coupling mechanism of human excitatory amino acid transporters.,Canul-Tec JC, Kumar A, Dhenin J, Assal R, Legrand P, Rey M, Chamot-Rooke J, Reyes N EMBO J. 2021 Nov 8:e108341. doi: 10.15252/embj.2021108341. PMID:34747040[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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