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Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport
Human excitatory amino acid transporter 3 (hEAAT3) mediates glutamate uptake in neurons, intestine, and kidney. Here, we report cryo-EM structures of hEAAT3 in several functional states where the transporter is empty, bound to coupled sodium ions only, or fully loaded with three sodium ions, a proto...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929514/ https://www.ncbi.nlm.nih.gov/pubmed/33658209 http://dx.doi.org/10.1126/sciadv.abf5814 |
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author | Qiu, Biao Matthies, Doreen Fortea, Eva Yu, Zhiheng Boudker, Olga |
author_facet | Qiu, Biao Matthies, Doreen Fortea, Eva Yu, Zhiheng Boudker, Olga |
author_sort | Qiu, Biao |
collection | PubMed |
description | Human excitatory amino acid transporter 3 (hEAAT3) mediates glutamate uptake in neurons, intestine, and kidney. Here, we report cryo-EM structures of hEAAT3 in several functional states where the transporter is empty, bound to coupled sodium ions only, or fully loaded with three sodium ions, a proton, and the substrate aspartate. The structures suggest that hEAAT3 operates by an elevator mechanism involving three functionally independent subunits. When the substrate-binding site is near the cytoplasm, it has a remarkably low affinity for the substrate, perhaps facilitating its release and allowing the rapid transport turnover. The mechanism of the coupled uptake of the sodium ions and the substrate is conserved across evolutionarily distant families and is augmented by coupling to protons in EAATs. The structures further suggest a mechanism by which a conserved glutamate residue mediates proton symport. |
format | Online Article Text |
id | pubmed-7929514 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-79295142021-03-11 Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport Qiu, Biao Matthies, Doreen Fortea, Eva Yu, Zhiheng Boudker, Olga Sci Adv Research Articles Human excitatory amino acid transporter 3 (hEAAT3) mediates glutamate uptake in neurons, intestine, and kidney. Here, we report cryo-EM structures of hEAAT3 in several functional states where the transporter is empty, bound to coupled sodium ions only, or fully loaded with three sodium ions, a proton, and the substrate aspartate. The structures suggest that hEAAT3 operates by an elevator mechanism involving three functionally independent subunits. When the substrate-binding site is near the cytoplasm, it has a remarkably low affinity for the substrate, perhaps facilitating its release and allowing the rapid transport turnover. The mechanism of the coupled uptake of the sodium ions and the substrate is conserved across evolutionarily distant families and is augmented by coupling to protons in EAATs. The structures further suggest a mechanism by which a conserved glutamate residue mediates proton symport. American Association for the Advancement of Science 2021-03-03 /pmc/articles/PMC7929514/ /pubmed/33658209 http://dx.doi.org/10.1126/sciadv.abf5814 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Qiu, Biao Matthies, Doreen Fortea, Eva Yu, Zhiheng Boudker, Olga Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport |
title | Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport |
title_full | Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport |
title_fullStr | Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport |
title_full_unstemmed | Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport |
title_short | Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport |
title_sort | cryo-em structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929514/ https://www.ncbi.nlm.nih.gov/pubmed/33658209 http://dx.doi.org/10.1126/sciadv.abf5814 |
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