ArticleProceedings of the National Academy of Sciences of the United States of America2009
Inward-facing conformation of glutamate transporters as revealed by their inverted-topology structural repeats.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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92 citing papers in PubMed, 144 citations in OpenAlex.
- Folding and Oligomerization of CLC Channels and Transporters.Chemical reviews · 2026Review
- SLC26A11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport.Nature communications · 2026Article
- Evolutionary analysis reveals the origin of sodium coupling in glutamate transporters.Nature structural & molecular biology · 2025Article
- Memorization bias impacts modeling of alternative conformational states of solute carrier membrane proteins with methods from deep learning.PLoS computational biology · 2025Article
- Memorization Bias Impacts Modeling of Alternative Conformational States of Symmetric Solute Carrier Membrane Proteins with Methods from Deep Learning.bioRxiv : the preprint server for biology · 2025Article
- Receptor-recognition and antiviral mechanisms of retrovirus-derived human proteins.Nature structural & molecular biology · 2024Article
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- Uptake mechanism of iron-phytosiderophore from the soil based on the structure of yellow stripe transporter.Nature communications · 2022Article
- Structural and mechanistic analysis of a tripartite ATP-independent periplasmic TRAP transporter.Nature communications · 2022Article
- General principles of secondary active transporter function.Biophysics reviews · 2022Review
- The ion-coupling mechanism of human excitatory amino acid transporters.The EMBO journal · 2022Article
- Pre-Steady-State Kinetics and Reverse Transport in Rat Glutamate Transporter EAAC1 with an Immobilized Transport Domain.Neurochemical research · 2022Article
- On the Role of a Conserved Methionine in the NaNeurochemical research · 2022Article
- Molecular Basis of Coupled Transport and Anion Conduction in Excitatory Amino Acid Transporters.Neurochemical research · 2022Review
- Linking function to global and local dynamics in an elevator-type transporter.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Critical amino acids in the TM2 of EAAT2 are essential for membrane-bound localization, substrate binding, transporter function and anion currents.Journal of cellular and molecular medicine · 2021Article
- The high-energy transition state of the glutamate transporter homologue GltPh.The EMBO journal · 2021Article
- The Conformationally Sensitive Spatial Distance Between the TM3-4 Loop and Transmembrane Segment 7 in the Glutamate Transporter Revealed by Paired-Cysteine Mutagenesis.Frontiers in cell and developmental biology · 2021Article
32 more citing papers are in PubMed but not listed here.
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4 authors at 2 institutions in 2 countries.
Funding
Abstract
Glutamate transporters regulate synaptic concentrations of this neurotransmitter by coupling its flux to that of sodium and other cations. Available crystal structures of an archeal homologue of these transporters, GltPh, resemble an extracellular-facing state, in which the bound substrate is occluded only by a small helical hairpin segment called HP2. However, a pathway to the cytoplasmic side of the membrane is not clearly apparent. We previously modeled an alternate state of a transporter from the neurotransmitter:sodium symporter family, which has an entirely different fold, solely on the presence of inverted-topology structural repeats. In GltPh, we identified two distinct sets of inverted-topology repeats and used these repeats to model an inward-facing conformation of the protein. To test this model, we introduced pairs of cysteines into the neuronal glutamate transporter EAAC1, at positions that are >27 A apart in the crystal structures of GltPh, but approximately = 10 A apart in the inward-facing model. Transport by these mutants was activated by pretreatment with the reducing agent dithithreitol. Subsequent treatment with the oxidizing agent copper(II)(1,10-phenantroline)(3) abolished this activation. The inhibition of transport was potentiated under conditions thought to promote the inward-facing conformation of the transporter. By contrast, the inhibition was reduced in the presence of the nontransportable substrate analogue D,L-threo-beta-benzyloxyaspartate, which favors the outward-facing conformation. Other conformation-sensitive accessibility measurements are also accommodated by our inward-facing model. These results suggest that the inclusion of inverted-topology repeats in transporters may provide a general solution to the requirement for two symmetry-related states in a single protein.
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