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

• Published in: Nature communications 2019-07, Vol.10 (1), p.3427-8, Article 3427
• Main Authors: Garaeva, Alisa A., Guskov, Albert, Slotboom, Dirk J., Paulino, Cristina
• Format: Article
• Language: English
• Subjects: 101/28; 631/45/173; 631/45/535/1258/1259; 631/535/1258/1259; 692/4028/67; 82/80; 82/83; Acids; Alanine; Allosteric properties; Amino Acid Sequence; Amino Acid Transport System ASC - metabolism; Amino acids; Binding sites; Binding Sites - genetics; Cell membranes; Conformation; Cryoelectron Microscopy; Humanities and Social Sciences; Humans; Membrane Transport Proteins - metabolism; Minor Histocompatibility Antigens - metabolism; multidisciplinary; Protein Domains; Protein Structure, Secondary; Protein Transport - physiology; Science; Science (multidisciplinary); Serine; Structural members; Substrate Specificity; Substrates
• ISSN: 2041-1723; 2041-1723
• 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. How the human Alanine Serine Cysteine Transporter 2 (ASCT2) binds its substrates, neutral amino acids, and releases them on the cytoplasmic side remains unclear. Here authors present an inward-open structure of the human ASCT2 which shows that a hairpin serves as a gate in the inward-facing state.