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Interdomain-linkers control conformational transitions in the SLC23 elevator transporter UraA

Author

Listed:
  • Benedikt T. Kuhn

    (Goethe University Frankfurt
    Max Planck Institute of Molecular Cell Biology and Genetics)

  • Jonathan Zöller

    (Max Planck Institute of Biophysics)

  • Iwan Zimmermann

    (University of Zurich)

  • Tim Gemeinhardt

    (Goethe University Frankfurt)

  • Dogukan H. Özkul

    (Goethe University Frankfurt)

  • Julian D. Langer

    (Max Planck Institute of Biophysics
    Max Planck Institute for Brain Research)

  • Markus A. Seeger

    (University of Zurich)

  • Eric R. Geertsma

    (Goethe University Frankfurt
    Max Planck Institute of Molecular Cell Biology and Genetics)

Abstract

Uptake of nucleobases and ascorbate is an essential process in all living organisms mediated by SLC23 transport proteins. These transmembrane carriers operate via the elevator alternating-access mechanism, and are composed of two rigid domains whose relative motion drives transport. The lack of large conformational changes within these domains suggests that the interdomain-linkers act as flexible tethers. Here, we show that interdomain-linkers are not mere tethers, but have a key regulatory role in dictating the conformational space of the transporter and defining the rotation axis of the mobile transport domain. By resolving a wide inward-open conformation of the SLC23 elevator transporter UraA and combining biochemical studies using a synthetic nanobody as conformational probe with hydrogen-deuterium exchange mass spectrometry, we demonstrate that interdomain-linkers control the function of transport proteins by influencing substrate affinity and transport rate. These findings open the possibility to allosterically modulate the activity of elevator proteins by targeting their linkers.

Suggested Citation

  • Benedikt T. Kuhn & Jonathan Zöller & Iwan Zimmermann & Tim Gemeinhardt & Dogukan H. Özkul & Julian D. Langer & Markus A. Seeger & Eric R. Geertsma, 2024. "Interdomain-linkers control conformational transitions in the SLC23 elevator transporter UraA," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51814-8
    DOI: 10.1038/s41467-024-51814-8
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