1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Structure and ion-release mechanism of PIB-4-type ATPases

  1. Christina Grønberg
  2. Qiaoxia Hu
  3. Dhani Ram Mahato
  4. Elena Longhin
  5. Nina Salustros
  6. Annette Duelli
  7. Pin Lyu
  8. Viktoria Bågenholm
  9. Jonas Eriksson
  10. Komal Umashankar Rao
  11. Domhnall Iain Henderson
  12. Gabriele Meloni
  13. Magnus Andersson
  14. Tristan Croll
  15. Gabriela Godaly
  16. Kaituo Wang
  17. Pontus Gourdon  Is a corresponding author
  1. University of Copenhagen, Denmark
  2. Umeå University, Sweden
  3. Lund University, Sweden
  4. The University of Texas at Dallas, United States
  5. University of Cambridge, United Kingdom
Research Article
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Cite this article as: eLife 2021;10:e73124 doi: 10.7554/eLife.73124

Abstract

Transition metals, such as zinc, are essential micronutrients in all organisms, but also highly toxic in excessive amounts. Heavy-metal transporting P-type (PIB) ATPases are crucial for homeostasis, conferring cellular detoxification and redistribution through transport of these ions across cellular membranes. No structural information is available for the PIB-4-ATPases, the subclass with the broadest cargo scope, and hence even their topology remains elusive. Here we present structures and complementary functional analyses of an archetypal PIB‑4‑ATPase, sCoaT from Sulfitobacter sp. NAS14-1. The data disclose the architecture, devoid of classical so-called heavy metal binding domains, and provides fundamentally new insights into the mechanism and diversity of heavy-metal transporters. We reveal several novel P-type ATPase features, including a dual role in heavy-metal release and as an internal counter ion of an invariant histidine. We also establish that the turn-over of PIB‑ATPases is potassium independent, contrasting to many other P-type ATPases. Combined with new inhibitory compounds, our results open up for efforts in e.g. drug discovery, since PIB-4-ATPases function as virulence factors in many pathogens.

Data availability

Atomic coordinates and structure factors for the sCoaT AlF4-- and BeF3--stabilized crystal structures have been deposited at the Protein Data Bank (PDB) under accession codes 7QBZ and 7QC0.

The following data sets were generated

Article and author information

Author details

  1. Christina Grønberg

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  2. Qiaoxia Hu

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  3. Dhani Ram Mahato

    Department of Chemistry, Umeå University, Umeå, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1121-7761
  4. Elena Longhin

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  5. Nina Salustros

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Annette Duelli

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Pin Lyu

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  8. Viktoria Bågenholm

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  9. Jonas Eriksson

    Department of Chemistry, Umeå University, Umeå, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  10. Komal Umashankar Rao

    Department of Laboratory Medicine, Lund University, Lund, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  11. Domhnall Iain Henderson

    Department of Laboratory Medicine, Lund University, Lund, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  12. Gabriele Meloni

    Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4976-1401
  13. Magnus Andersson

    Department of Chemistry, Umeå University, Umeå, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  14. Tristan Croll

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Gabriela Godaly

    Department of Laboratory Medicine, Umeå University, Umeå, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3467-1350
  16. Kaituo Wang

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  17. Pontus Gourdon

    Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
    For correspondence
    pontus@sund.ku.dk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8631-3539

Funding

Novo Nordisk Fonden (NNF18SA0034956)

  • Christina Grønberg

Lundbeckfonden (R313-2019-774,R218-2016-1548,R133-A12689)

  • Pontus Gourdon

Knut och Alice Wallenbergs Stiftelse (2020.0194,2015.0131)

  • Pontus Gourdon

Carlsbergfondet (CF15-0542,2013_01_0641)

  • Pontus Gourdon

Novo Nordisk Fonden (NNF13OC0007471)

  • Pontus Gourdon

Brodrene Hartmann (A29519)

  • Pontus Gourdon

Agnes og Poul Friis Fond

  • Pontus Gourdon

Augustinus Fonden (16-1992)

  • Pontus Gourdon

Crafoord (20180652,20170818)

  • Pontus Gourdon

Per-Eric and Ulla Schyberg (38267)

  • Pontus Gourdon

Swedish Research Council (2016-04474)

  • Pontus Gourdon

The memorial foundation of manufacturer Vilhelm Pedersen and wife - and the Aarhus Wilson consortium

  • Christina Grønberg

The Independent Research Fund Denmark (9039-00273A)

  • Pontus Gourdon

China Scholarship Council

  • Qiaoxia Hu

Carl Tryggers Stiftelse för Vetenskaplig Forskning (CTS 17:22)

  • Dhani Ram Mahato

Swedish Research Council Starting Grant (2016-03610)

  • Magnus Andersson

Robert A. Welke Cancer Research Foundation (AT-1935-20170325 and AT-2073-20210327)

  • Gabriele Meloni

National Institute of General Medical Sciences (R35GM128704))

  • Gabriele Meloni

National Science Foundation (CHE- 2045984)

  • Gabriele Meloni

Swedish Heart-Lung Foundation (20200378)

  • Gabriela Godaly

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Merritt Maduke, Stanford University School of Medicine, United States

Publication history

  1. Received: August 17, 2021
  2. Accepted: December 17, 2021
  3. Accepted Manuscript published: December 24, 2021 (version 1)

Copyright

© 2021, Grønberg et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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