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Na+-dependent gate dynamics and electrostatic attraction ensure substrate coupling in glutamate transporters. 2020

C Alleva, and K Kovalev, and R Astashkin, and M I Berndt, and C Baeken, and T Balandin, and V Gordeliy, and Ch Fahlke, and J-P Machtens
Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, Jülich, Germany.

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.

UI MeSH Term Description Entries
D007477 Ions An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as CATIONS; those with a negative charge are ANIONS.
D012964 Sodium A member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. Sodium Ion Level,Sodium-23,Ion Level, Sodium,Level, Sodium Ion,Sodium 23
D055672 Static Electricity The accumulation of an electric charge on a object Electrostatic,Electrostatics,Static Charge,Charge, Static,Charges, Static,Electricity, Static,Static Charges
D018698 Glutamic Acid A non-essential amino acid naturally occurring in the L-form. Glutamic acid is the most common excitatory neurotransmitter in the CENTRAL NERVOUS SYSTEM. Aluminum L-Glutamate,Glutamate,Potassium Glutamate,D-Glutamate,Glutamic Acid, (D)-Isomer,L-Glutamate,L-Glutamic Acid,Aluminum L Glutamate,D Glutamate,Glutamate, Potassium,L Glutamate,L Glutamic Acid,L-Glutamate, Aluminum
D027322 Amino Acid Transport System X-AG A family of POTASSIUM and SODIUM-dependent acidic amino acid transporters that demonstrate a high affinity for GLUTAMIC ACID and ASPARTIC ACID. Several variants of this system are found in neuronal tissue. Glutamate-Aspartate Transporter,Amino Acid Transport System XAG,GLAST Glutamate-Aspartate Transporters,Glutamate Translocase,Glutamate Transport Glycoprotein,Glutamate Transporter,Amino Acid Transport System X AG,GLAST Glutamate Aspartate Transporters,Glutamate Aspartate Transporter,Glutamate-Aspartate Transporters, GLAST,Transport Glycoprotein, Glutamate,Transporter, Glutamate-Aspartate,Transporters, GLAST Glutamate-Aspartate

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