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

Alisa A. Garaeva, Albert Guskov, Dirk J. Slotboom, Cristina Paulino*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

33 Citaten (Scopus)
188 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Artikelnummer3427
Aantal pagina's8
TijdschriftNature Communications
Volume10
DOI's
StatusPublished - 31-jul-2019

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