Structural basis of excitatory amino acid transporter 3 substrate recognition.

ABSTRACT: Excitatory amino acid transporters (EAATs) reside on cell surfaces and uptake substrates, including L-glutamate, L-aspartate, and D-aspartate, using ion gradients. Among five EAATs, EAAT3 is the only isoform that can efficiently transport L-cysteine, a substrate for glutathione synthesis. Recent studies suggest that EAAT3 also transports the oncometabolite R-2-hydroxyglutarate (R-2HG). Here, we examined the structural basis of substrate recognition by determining the cryogenic electron microscopy (cryo-EM) structures of EAAT3 bound to different substrates. We found that L-cysteine binds to EAAT3 in thiolate form, and EAAT3 recognizes different substrates by fine-tuning local conformations of the coordinating residues. However, using purified human EAAT3, we could not observe R-2HG binding

SUBMITTER: Qiu B 

PROVIDER: S-EPMC12036983 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature