A one-gate elevator mechanism for the human neutral amino acid transporter ASCT2
By A. Garaeva, A. Guskov, D. Slotboom, C. Paulino. 2019
101 citations recorded by the source corpus.
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.
Subfields: Biochemistry, Molecular Biology, Oncology
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In Molecular Biology
- Diego del Alamo
- Jens Meiler
- Avner Schlessinger
- Massimiliano Bonomi
- Davide Sala
- Hassane S. Mchaourab
- Burkhard Rost
- Björn Wallner
In Oncology
Citations in the corpus
- Sampling alternative conformational states of transporters and receptors with AlphaFold2 (2022, background): “…characterized in the literature ( Drew and Boudker, 2016 ), including rocking-bundle (LAT1, Yan et al., 2019 ; Yan et al., 2021 ; ZnT8, Xue et al., 2020 ), rocker-switch (MCT1, Wang et al., 2021 ; STP10, Bavnhøj et al., 2021 ), and elevator (ASCT2, Garibsingh et al., 2021 ; Garaeva et al., 2019 ).”
- Rational design of ASCT2 inhibitors using an integrated experimental-computational approach (2021, background): “Both the inwardopen and outward-occluded structures of hASCT2 showed a putative cholesterol binding site at the interface between mobile transport and the static scaffold domains (18, 20).”