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TitleA one-gate elevator mechanism for the human neutral amino acid transporter ASCT2.
Journal, issue, pagesNat Commun, Vol. 10, Issue 1, Page 3427, Year 2019
Publish dateJul 31, 2019
AuthorsAlisa A Garaeva / Albert Guskov / Dirk J Slotboom / Cristina Paulino /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:31366933 / PubMed Central
MethodsEM (single particle)
Resolution3.61 - 6.98 Å
Structure data

10016

6rvx

EMDB-10016, PDB-6rvx:
Inward-open structure of the ASCT2 (SLC1A5) mutant C467R in presence of TBOA
Method: EM (single particle) / Resolution: 3.61 Å

EMDB-10017:
Inward-open structure of the ASCT2 (SLC1A5) in absence of substrate
Method: EM (single particle) / Resolution: 6.98 Å

10018

6rvy

EMDB-10018, PDB-6rvy:
Inward-open structure of the ASCT2 (SLC1A5) mutant C467R in absence of substrate
Method: EM (single particle) / Resolution: 4.13 Å

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / solute carrier family 1 (SLC1A) one-gate elevator mechanism neutral amino acid exchange membrane protein cryo-EM / solute carrier family 1 (SLC1A) one-gate elevator mechanism neutral amino acid exchange membrane proteins cryo-EM

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