Journal Article

FZJ-2020-03832

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Na + -dependent gate dynamics and electrostatic attraction ensure substrate coupling in glutamate transporters

Fahlke, C. (Corresponding author)FZJ* ; Balandin, T.FZJ* ; Astashkin, R. ; Alleva, C.FZJ* ; Machtens, J.-P. (Corresponding author)FZJ* ; Gordeliy, V.FZJ* ; Baeken, C.FZJ* ; Kovalev, K.FZJ* ; Berndt, M.FZJ*

2020
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: http://hdl.handle.net/2128/26324  doi:10.1126/sciadv.aba9854

Abstract: Excitatory amino acid transporters (EAATs) harness [Na+], [K+], and [H+] gradients for fast and efficient glutamate removal from the synaptic cleft. Since each glutamate is cotransported with three Na+ ions, [Na+] gradients are the predominant driving force for glutamate uptake. We combined all-atom molecular dynamics simulations, fluorescence spectroscopy, and x-ray crystallography to study Na+:substrate coupling in the EAAT homolog GltPh. A lipidic cubic phase x-ray crystal structure of wild-type, Na+-only bound GltPh at 2.5-Å resolution revealed the fully open, outward-facing state primed for subsequent substrate binding. Simulations and kinetic experiments established that only the binding of two Na+ ions to the Na1 and Na3 sites ensures complete HP2 gate opening via a conformational selection-like mechanism and enables high-affinity substrate binding via electrostatic attraction. The combination of Na+-stabilized gate opening and electrostatic coupling of aspartate to Na+ binding provides a constant Na+:substrate transport stoichiometry over a broad range of neurotransmitter concentrations.

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)
2. Strukturbiochemie (IBI-7)
3. JARA - HPC (JARA-HPC)

Research Program(s):

1. 551 - Functional Macromolecules and Complexes (POF3-551) (POF3-551)
2. MOLECULAR MODELLING OF BIFUNCTIONAL MEMBRANE TRANSPORT PROTEINS (jics40_20190501) (jics40_20190501)
3. Molecular dynamics simulations of P2X receptors (jara0180_20200501) (jara0180_20200501)
4. Multiscale simulations of voltage-gated sodium channel complexes and clusters (jics42_20191101) (jics42_20191101)
5. Molecular dynamics of the SLC26 family of ion channels and transporters (jara0177_20191101) (jara0177_20191101)

Appears in the scientific report 2020

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