Allosteric gate modulation confers K+ coupling in glutamate transporters

• Daniel Kortzak ^[1] ; Claudia Alleva ^[1] ; Ingo Weyand ^[1] ; David Ewers ^[2] ; Meike I Zimmermann ^[1] ; Arne Franzen ^[1] ; Jan‐Philipp Machtens ^[3] ; Christoph Fahlke ^[1]
  1. [1] 1 Institute of Complex Systems Zelluläre Biophysik (ICS‐4) and JARA‐HPC Forschungszentrum Jülich Jülich Germany
  2. [2] 1 Institute of Complex Systems Zelluläre Biophysik (ICS‐4) and JARA‐HPC Forschungszentrum Jülich Jülich Germany; 2 Klinik für klinische Neurophysiologie Universitätsmedizin Göttingen Göttingen Germany; 3 Abteilung für Neurogenetik Max‐Planck‐Institut für Experimentelle Medizin Göttingen Germany
  3. [3] 1 Institute of Complex Systems Zelluläre Biophysik (ICS‐4) and JARA‐HPC Forschungszentrum Jülich Jülich Germany; 4 Department of Molecular Pharmacology RWTH Aachen University Aachen Germany

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 19, 2019
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • Excitatory amino acid transporters (EAATs) mediate glial and neuronal glutamate uptake to terminate synaptic transmission and to ensure low resting glutamate concentrations. Effective glutamate uptake is achieved by cotransport with 3 Na+ and 1 H+, in exchange with 1 K+. The underlying principles of this complex transport stoichiometry remain poorly understood. We use molecular dynamics simulations and electrophysiological experiments to elucidate how mammalian EAATs harness K+ gradients, unlike their K+‐independent prokaryotic homologues. Glutamate transport is achieved via elevator‐like translocation of the transport domain. In EAATs, glutamate‐free re‐translocation is prevented by an external gate remaining open until K+ binding closes and locks the gate. Prokaryotic GltPh contains the same K+‐binding site, but the gate can close without K+. Our study provides a comprehensive description of K+‐dependent glutamate transport and reveals a hitherto unknown allosteric coupling mechanism that permits adaptions of the transport stoichiometry without affecting ion or substrate binding.