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Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2

Author

Listed:
  • Huanyu Z. Li

    (University of Oxford)

  • Ashley C. W. Pike

    (University of Oxford)

  • Irina Lotsaris

    (University of Sydney)

  • Gamma Chi

    (University of Oxford)

  • Jesper S. Hansen

    (University of Oxford)

  • Sarah C. Lee

    (University of Birmingham)

  • Karin E. J. Rödström

    (University of Oxford)

  • Simon R. Bushell

    (University of Oxford)

  • David Speedman

    (University of Oxford)

  • Adam Evans

    (University of Oxford)

  • Dong Wang

    (University of Oxford)

  • Didi He

    (University of Oxford)

  • Leela Shrestha

    (University of Oxford)

  • Chady Nasrallah

    (University of Oxford)

  • Nicola A. Burgess-Brown

    (University of Oxford)

  • Robert J. Vandenberg

    (University of Sydney)

  • Timothy R. Dafforn

    (University of Birmingham)

  • Elisabeth P. Carpenter

    (University of Oxford)

  • David B. Sauer

    (University of Oxford)

Abstract

Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, the secondary amino acid modulates neurotransmission and regulates the kinetics of signaling proteins. To understand the structural basis of proline import, we solved the structure of the proline transporter SIT1 in complex with the COVID-19 viral receptor ACE2 by cryo-electron microscopy. The structure of pipecolate-bound SIT1 reveals the specific sequence requirements for proline transport in the SLC6 family and how this protein excludes amino acids with extended side chains. By comparing apo and substrate-bound SIT1 states, we also identify the structural changes that link substrate release and opening of the cytoplasmic gate and provide an explanation for how a missense mutation in the transporter causes iminoglycinuria.

Suggested Citation

  • Huanyu Z. Li & Ashley C. W. Pike & Irina Lotsaris & Gamma Chi & Jesper S. Hansen & Sarah C. Lee & Karin E. J. Rödström & Simon R. Bushell & David Speedman & Adam Evans & Dong Wang & Didi He & Leela Sh, 2024. "Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48921-x
    DOI: 10.1038/s41467-024-48921-x
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