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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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    1. Zenia Motiwala & Nanda Gowtham Aduri & Hamidreza Shaye & Gye Won Han & Jordy Homing Lam & Vsevolod Katritch & Vadim Cherezov & Cornelius Gati, 2022. "Structural basis of GABA reuptake inhibition," Nature, Nature, vol. 606(7915), pages 820-826, June.
    2. Zenia Motiwala & Nanda Gowtham Aduri & Hamidreza Shaye & Gye Won Han & Jordy Homing Lam & Vsevolod Katritch & Vadim Cherezov & Cornelius Gati, 2022. "Publisher Correction: Structural basis of GABA reuptake inhibition," Nature, Nature, vol. 608(7921), pages 15-15, August.
    3. Harini Krishnamurthy & Eric Gouaux, 2012. "X-ray structures of LeuT in substrate-free outward-open and apo inward-open states," Nature, Nature, vol. 481(7382), pages 469-474, January.
    4. Kamil Gotfryd & Thomas Boesen & Jonas S. Mortensen & George Khelashvili & Matthias Quick & Daniel S. Terry & Julie W. Missel & Michael V. LeVine & Pontus Gourdon & Scott C. Blanchard & Jonathan A. Jav, 2020. "X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    5. Yongfang Zhao & Daniel Terry & Lei Shi & Harel Weinstein & Scott C. Blanchard & Jonathan A. Javitch, 2010. "Single-molecule dynamics of gating in a neurotransmitter transporter homologue," Nature, Nature, vol. 465(7295), pages 188-193, May.
    6. Min Jin Ha & Francesco Claudio Stingo & Veerabhadran Baladandayuthapani, 2021. "Bayesian Structure Learning in Multilayered Genomic Networks," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 116(534), pages 605-618, April.
    7. David B. Sauer & Jinmei Song & Bing Wang & Jacob K. Hilton & Nathan K. Karpowich & Joseph A. Mindell & William J. Rice & Da-Neng Wang, 2021. "Structure and inhibition mechanism of the human citrate transporter NaCT," Nature, Nature, vol. 591(7848), pages 157-161, March.
    8. Aravind Penmatsa & Kevin H. Wang & Eric Gouaux, 2013. "X-ray structure of dopamine transporter elucidates antidepressant mechanism," Nature, Nature, vol. 503(7474), pages 85-90, November.
    9. Jonathan A. Coleman & Evan M. Green & Eric Gouaux, 2016. "X-ray structures and mechanism of the human serotonin transporter," Nature, Nature, vol. 532(7599), pages 334-339, April.
    10. Xianyong Yin & Lap Sum Chan & Debraj Bose & Anne U. Jackson & Peter VandeHaar & Adam E. Locke & Christian Fuchsberger & Heather M. Stringham & Ryan Welch & Ketian Yu & Lilian Fernandes Silva & Susan K, 2022. "Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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