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

Alisa A. Garaeva, Albert Guskov, Dirk J. Slotboom () and Cristina Paulino ()
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Alisa A. Garaeva: University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute
Albert Guskov: University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute
Dirk J. Slotboom: University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute
Cristina Paulino: University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11363-x

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