Titel
Refinement of the Central Steps of Substrate Transport by the Aspartate Transporter GltPh: Elucidating the Role of the Na2 Sodium Binding Site
Autor*in
SanthoshKannan Venkatesan
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna
Autor*in
Kusumika Saha
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna
Autor*in
Azmat Sohail
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna
... show all
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.
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
https://phaidra.univie.ac.at/o:448494
Erschienen in
Titel
PLOS Computational Biology
Band
11
Ausgabe
10
Verlag
Public Library of Science (PLoS)
Erscheinungsdatum
2015
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