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Cryo-EM structure of the human Asc-1 transporter complex

Author

Listed:
  • Yaning Li

    (Southern University of Science and Technology
    Southern University of Science and Technology
    Tsinghua University)

  • Yingying Guo

    (Southern University of Science and Technology)

  • Angelika Bröer

    (Australian National University)

  • Lu Dai

    (Southern University of Science and Technology)

  • Stefan Brӧer

    (Australian National University)

  • Renhong Yan

    (Southern University of Science and Technology)

Abstract

The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium-independent transport of small neutral amino acids, including L-Alanine (L-Ala), Glycine (Gly), and D-Serine (D-Ser), within the central nervous system (CNS). D-Ser and Gly are two key endogenous glutamate co-agonists that activate N-methyl-d-aspartate (NMDA) receptors by binding to the allosteric site. Mice deficient in Asc-1 display severe symptoms such as tremors, ataxia, and seizures, leading to early postnatal death. Despite its physiological importance, the functional mechanism of the Asc-1-4F2hc complex has remained elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of the human Asc-1-4F2hc complex in its apo state, D-Ser bound state, and L-Ala bound state, resolved at 3.6 Å, 3.5 Å, and 3.4 Å, respectively. Through detailed structural analysis and transport assays, we uncover a comprehensive alternating access mechanism that underlies conformational changes in the complex. In summary, our findings reveal the architecture of the Asc-1 and 4F2hc complex and provide valuable insights into substrate recognition and the functional cycle of this essential transporter complex.

Suggested Citation

  • Yaning Li & Yingying Guo & Angelika Bröer & Lu Dai & Stefan Brӧer & Renhong Yan, 2024. "Cryo-EM structure of the human Asc-1 transporter complex," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47468-1
    DOI: 10.1038/s41467-024-47468-1
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    References listed on IDEAS

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    1. Xiang Gao & Lijun Zhou & Xuyao Jiao & Feiran Lu & Chuangye Yan & Xin Zeng & Jiawei Wang & Yigong Shi, 2010. "Mechanism of substrate recognition and transport by an amino acid antiporter," Nature, Nature, vol. 463(7282), pages 828-832, February.
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