Transport mechanism of a glutamate transporter homologue GltPh

Ji, Yurui; Postis, Vincent L. G.; Wang, Yingying; Bartlam, Mark; Goldman, Adrian

doi:10.1042/bst20160055

Cited by 15 publications

(10 citation statements)

References 47 publications

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“…The structure and function of SLC1 transporters have been studied using bacterial aspartate transporter homologues GltPH from Pyrococcus horikoshii (7)(8)(9)(10)(11)(12), GltTK from Thermococcus kodakarensis (13,14), human glutamate transporter SLC1A3 (15) and glutamine transporter SLC1A5 (16). All of these transporters form a trimer of independently functioning protomers that uses an elevator mechanism to carry amino acids across membranes (11,17).…”

mentioning

confidence: 99%

Structural basis for the transport mechanism of the human glutamine transporter SLC1A5 (ASCT2)

Plotnikova

Bonin

et al. 2019

Preprint

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Alanine-serine-cysteine transporter 2 (ASCT2, SLC1A5) is the primary transporter of glutamine in cancer cells and regulates the mTORC1 signaling pathway. The SLC1A5 function involves finely tuned orchestration of two domain movements that include the substrate-binding transport domain and the scaffold domain. Here, we present cryo-EM structures of human SLC1A5 and its complex with the substrate, L-glutamine in an outward-facing conformation. These structures reveal insights into the conformation of the critical ECL2a loop which connects the two domains, thus allowing rigid body movement of the transport domain throughout the transport cycle. Furthermore, the structures provide new insights into substrate recognition, which involves conformational changes in the HP2 loop. A putative cholesterol binding site was observed near the domain interface in the outward-facing state. Comparison with the previously determined inward-facing structure of SCL1A5 provides a basis for a more integrated understanding of substrate recognition and transport mechanism in the SLC1 family. Our structures are likely to aid the development of potent and selective SLC1A5 inhibitors for the treatment of cancer and autoimmune disorders.

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mentioning

confidence: 99%

Structural basis for the transport mechanism of the human glutamine transporter SLC1A5 (ASCT2)

Plotnikova

Bonin

et al. 2019

Preprint

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“…The chloride conduction pathway and the mechanism of anion permeation are still not completely understood. The anion selectivity of Glt Ph , the main subject of anion conductance studies, is almost identical with that of EAATs [46]. Chloride permeation occurs at the interface between the scaffold and transport domains, but it is not clear what conformational state mediates anion permeation nor exactly which residues are involved.…”

Section: Uncoupled Chloride Conductancementioning

confidence: 99%

Glutamate transporters: a broad review of the most recent archaeal and human structures

Pavić

Holmes

Postis

et al. 2019

Biochemical Society Transactions

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Glutamate transporters play important roles in bacteria, archaea and eukaryotes. Their function in the mammalian central nervous system is essential for preventing excitotoxicity, and their dysregulation is implicated in many diseases, such as epilepsy and Alzheimer's. Elucidating their transport mechanism would further the understanding of these transporters and promote drug design as they provide compelling targets for understanding the pathophysiology of diseases and may have a direct role in the treatment of conditions involving glutamate excitotoxicity. This review outlines the insights into the transport cycle, uncoupled chloride conductance and modulation, as well as identifying areas that require further investigation.*These authors contributed equally to this work.

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“…GltPh is an archaeal homologue of mammalian glutamate transporters that co-transports by symport an aspartate molecule together with sodium ions [24,25]. The favourable internalization of sodium through its electrochemical gradient provides energy for internalization of aspartate into the cytoplasm against its concentration gradient.…”

Section: Example 1: Gltph Shows Heterotropic Aspartate and Sodium Ionmentioning

confidence: 99%

Handling complexity in biological interactions

Vega

Abián

Velázquez‐Campoy

2019

J Therm Anal Calorim

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Biological processes rely on interactions between many binding partners. Binding results in the modulation of the conformational landscape of the interacting molecules, a phenomenon rooted in folding and binding cooperativity underlying the allosteric functional regulation of biomacromolecules. The conformational equilibrium of a protein and the binding equilibria of different interacting and cooperative ligands are coupled giving rise to a complex scenario in which protein function can be finely tuned and modulated. Binding cooperativity and allostery add additional levels of complexity in protein function regulation. Here we will review some important concepts associated with binding, cooperativity and allostery in protein interactions, illustrated with several representative protein-dependent biological systems related to drug discovery and physiological mechanisms characterization and studied by isothermal titration calorimetry.

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Transport mechanism of a glutamate transporter homologue GltPh

Cited by 15 publications

References 47 publications

Structural basis for the transport mechanism of the human glutamine transporter SLC1A5 (ASCT2)

Structural basis for the transport mechanism of the human glutamine transporter SLC1A5 (ASCT2)

Glutamate transporters: a broad review of the most recent archaeal and human structures

Handling complexity in biological interactions

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