Abstract
Glutamate homeostasis in the brain is maintained by glutamate transporter mediated accumulation. Impaired transport is associated with several neurological disorders, including stroke and amyotrophic lateral sclerosis. Crystal structures of the homolog transporter GltPh from Pyrococcus horikoshii revealed large structural changes. Substrate uptake at the atomic level and the mechanism of ion gradient conversion into directional transport remained enigmatic. We observed in repeated simulations that two local structural changes regulated transport. The first change led to formation of the transient Na2 sodium binding site, triggered by side chain rotation of T308. The second change destabilized cytoplasmic ionic interactions. We found that sodium binding to the transiently formed Na2 site energized substrate uptake through reshaping of the energy hypersurface. Uptake experiments in reconstituted proteoliposomes confirmed the proposed mechanism. We reproduced the results in the human glutamate transporter EAAT3 indicating a conserved mechanics from archaea to humans.
Highlights
Glutamate is the primary excitatory neurotransmitter in the central nervous system
We identified the structural changes that accompany substrate transport and convert the energy stored in the ion gradient into a directional transport
Dysfunction in Excitatory amino acid transporters (EAAT) has been implicated in several neurological diseases, which are associated with loss of neurons [5,6,7,8,9]
Summary
Glutamate is the primary excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporters (EAAT) are membrane proteins, which remove released glutamate from the synaptic cleft [1]. Substrate transport by the human EAATs is coupled to transport of three sodium ions and one proton followed by the counter-transport of one potassium ion [2,3,4]. Dysfunction in EAATs has been implicated in several neurological diseases, which are associated with loss of neurons (e.g., amyotrophic lateral sclerosis, Alzheimer’s disease, stroke, cerebral ischemia, traumatic brain injury, epilepsy and Huntington’s disease) [5,6,7,8,9]. Development of drugs, which could enhance EAAT transporter activity, would be beneficial for patients
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