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

Author

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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
    University of Groningen, Zernike Institute for Advanced Materials)

  • Cristina Paulino

    (University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute
    University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute)

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.

Suggested Citation

  • Alisa A. Garaeva & Albert Guskov & Dirk J. Slotboom & Cristina Paulino, 2019. "A one-gate elevator mechanism for the human neutral amino acid transporter ASCT2," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11363-x
    DOI: 10.1038/s41467-019-11363-x
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    Cited by:

    1. Takafumi Kato & Tsukasa Kusakizako & Chunhuan Jin & Xinyu Zhou & Ryuichi Ohgaki & LiLi Quan & Minhui Xu & Suguru Okuda & Kan Kobayashi & Keitaro Yamashita & Tomohiro Nishizawa & Yoshikatsu Kanai & Osa, 2022. "Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Zhenglai Zhang & Huiwen Chen & Ze Geng & Zhuoya Yu & Hang Li & Yanli Dong & Hongwei Zhang & Zhuo Huang & Juquan Jiang & Yan Zhao, 2022. "Structural basis of ligand binding modes of human EAAT2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Anna M. Borowska & Maria Gabriella Chiariello & Alisa A. Garaeva & Jan Rheinberger & Siewert J. Marrink & Cristina Paulino & Dirk J. Slotboom, 2024. "Structural basis of the obligatory exchange mode of human neutral amino acid transporter ASCT2," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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