Abstract
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 language | English |
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Article number | 3427 |
Number of pages | 8 |
Journal | Nature Communications |
Volume | 10 |
DOIs | |
Publication status | Published - 31-Jul-2019 |
Keywords
- CRYO-EM STRUCTURE
- CRYSTAL-STRUCTURE
- GLUTAMATE
- SUBSTRATE
- VISUALIZATION
- ORIENTATION
- HOMOLOG
- SYSTEM
- CANCER
- FELINE
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