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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)
235 Downloads (Pure)

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.

Original languageEnglish
Article number3427
Number of pages8
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 31-Jul-2019

Keywords

  • CRYO-EM STRUCTURE
  • CRYSTAL-STRUCTURE
  • GLUTAMATE
  • SUBSTRATE
  • VISUALIZATION
  • ORIENTATION
  • HOMOLOG
  • SYSTEM
  • CANCER
  • FELINE

Cite this