Publication

A one-gate elevator mechanism for the human neutral amino acid transporter ASCT2

Garaeva, A. A., Guskov, A., Slotboom, D. J. & Paulino, C., 31-Jul-2019, In : Nature Communications. 10, 8 p., 3427.

Research output: Contribution to journalArticleAcademicpeer-review

The human Alanine Serine Cysteine Transporter 2 (ASCT2) is a neutral amino acid exchanger that belongs to the solute carrier family 1 (SLC1A). SLC1A structures have revealed an elevator-type mechanism, in which the substrate is translocated across the cell membrane by a large displacement of the transport domain, whereas a small movement of hairpin 2 (HP2) gates the extracellular access to the substrate-binding site. However, it has remained unclear how substrate binding and release is gated on the cytoplasmic side. Here, we present an inward-open structure of the human ASCT2, revealing a hitherto elusive SLC1A conformation. Strikingly, the same structural element (HP2) serves as a gate in the inward-facing as in the outward-facing state. The structures reveal that SLC1A transporters work as one-gate elevators. Unassigned densities near the gate and surrounding the scaffold domain, may represent potential allosteric binding sites, which could guide the design of lipidic-inhibitors for anticancer therapy.

Original languageEnglish
Article number3427
Number of pages8
JournalNature Communications
Volume10
Publication statusPublished - 31-Jul-2019

    Keywords

  • CRYO-EM STRUCTURE, CRYSTAL-STRUCTURE, GLUTAMATE, SUBSTRATE, VISUALIZATION, ORIENTATION, HOMOLOG, SYSTEM, CANCER, FELINE
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