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Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation

Author

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  • Michael F. Fuss

    (Goethe University Frankfurt)

  • Jan-Philip Wieferig

    (Max Planck Institute of Biophysics)

  • Robin A. Corey

    (University of Oxford
    University of Bristol)

  • Yvonne Hellmich

    (Goethe University Frankfurt)

  • Igor Tascón

    (Goethe University Frankfurt
    University of the Basque Country
    Ikerbasque, Basque Foundation for Science)

  • Joana S. Sousa

    (Max Planck Institute of Biophysics
    UCB Pharma, UCB Biopharma UK)

  • Phillip J. Stansfeld

    (University of Warwick)

  • Janet Vonck

    (Max Planck Institute of Biophysics)

  • Inga Hänelt

    (Goethe University Frankfurt)

Abstract

Cyclic di-AMP is the only known essential second messenger in bacteria and archaea, regulating different proteins indispensable for numerous physiological processes. In particular, it controls various potassium and osmolyte transporters involved in osmoregulation. In Bacillus subtilis, the K+/H+ symporter KimA of the KUP family is inactivated by c-di-AMP. KimA sustains survival at potassium limitation at low external pH by mediating potassium ion uptake. However, at elevated intracellular K+ concentrations, further K+ accumulation would be toxic. In this study, we reveal the molecular basis of how c-di-AMP binding inhibits KimA. We report cryo-EM structures of KimA with bound c-di-AMP in detergent solution and reconstituted in amphipols. By combining structural data with functional assays and molecular dynamics simulations we reveal how c-di-AMP modulates transport. We show that an intracellular loop in the transmembrane domain interacts with c-di-AMP bound to the adjacent cytosolic domain. This reduces the mobility of transmembrane helices at the cytosolic side of the K+ binding site and therefore traps KimA in an inward-occluded conformation.

Suggested Citation

  • Michael F. Fuss & Jan-Philip Wieferig & Robin A. Corey & Yvonne Hellmich & Igor Tascón & Joana S. Sousa & Phillip J. Stansfeld & Janet Vonck & Inga Hänelt, 2023. "Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38944-1
    DOI: 10.1038/s41467-023-38944-1
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    1. Alexey Rozov & Iskander Khusainov & Kamel El Omari & Ramona Duman & Vitaliy Mykhaylyk & Marat Yusupov & Eric Westhof & Armin Wagner & Gulnara Yusupova, 2019. "Importance of potassium ions for ribosome structure and function revealed by long-wavelength X-ray diffraction," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Arthur Prindle & Jintao Liu & Munehiro Asally & San Ly & Jordi Garcia-Ojalvo & Gürol M. Süel, 2015. "Ion channels enable electrical communication in bacterial communities," Nature, Nature, vol. 527(7576), pages 59-63, November.
    3. Ekaitz Errasti-Murugarren & Joana Fort & Paola Bartoccioni & Lucía Díaz & Els Pardon & Xavier Carpena & Meritxell Espino-Guarch & Antonio Zorzano & Christine Ziegler & Jan Steyaert & Juan Fernández-Re, 2019. "L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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    1. Jakob M. Silberberg & Sophie Ketter & Paul J. N. Böhm & Kristin Jordan & Marcel Wittenberg & Julia Grass & Inga Hänelt, 2024. "KdpD is a tandem serine histidine kinase that controls K+ pump KdpFABC transcriptionally and post-translationally," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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