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

Nat Commun. 2019 Jul 31;10(1):3427. doi: 10.1038/s41467-019-11363-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Transport System ASC / metabolism*
  • Binding Sites / genetics
  • Cryoelectron Microscopy
  • Humans
  • Membrane Transport Proteins / metabolism*
  • Minor Histocompatibility Antigens / metabolism*
  • Protein Domains
  • Protein Structure, Secondary
  • Protein Transport / physiology
  • Substrate Specificity


  • Amino Acid Transport System ASC
  • Membrane Transport Proteins
  • Minor Histocompatibility Antigens
  • SLC1A5 protein, human