Journal Article

FZJ-2019-04644

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Allosteric gate modulation confers K + coupling in glutamate transporters

Kortzak, D.FZJ* ; Alleva, C.FZJ* ; Weyand, I.FZJ* ; Ewers, D. ; Zimmermann, M. I.FZJ* ; Franzen, A.FZJ* ; Machtens, J.FZJ* ; Fahlke, C. (Corresponding author)FZJ*

2019
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: http://hdl.handle.net/2128/24965  doi:10.15252/embj.2019101468

Abstract: Excitatory amino acid transporters (EAAT s) 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 EAAT s harness K+ gradients, unlike their K+‐independent prokaryotic homologues. Glutamate transport is achieved via elevator‐like translocation of the transport domain. In EAAT s, 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.

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Contributing Institute(s):

1. Zelluläre Biophysik (ICS-4)
2. JARA - HPC (JARA-HPC)

Research Program(s):

1. 551 - Functional Macromolecules and Complexes (POF3-551) (POF3-551)
2. Mechanisms of Ca2+-activated Cl- channels and lipid scramblases of the TMEM16 family (jics41_20161101) (jics41_20161101)
3. Molecular dynamics of the SLC26 family of ion channels and transporters (jara0177_20171101) (jara0177_20171101)
4. Multiscale simulations of voltage-gated sodium channel complexes and clusters (jics42_20181101) (jics42_20181101)
5. MOLECULAR MODELLING OF BIFUNCTIONAL MEMBRANE TRANSPORT PROTEINS (jics40_20190501) (jics40_20190501)
6. Molecular dynamics simulations of P2X receptors (jara0180_20200501) (jara0180_20200501)

Appears in the scientific report 2020

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