4.8 Article

Structure and ion-release mechanism of PIB-4-type ATPases

期刊

ELIFE
卷 10, 期 -, 页码 -

出版社

eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.73124

关键词

P-type ATPase; x-ray crystallography; sulfitobacter sp; NAS14-1; transition metals; PIB-4-ATPase; Other

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资金

  1. Novo Nordisk Foundation [NNF18SA0034956]
  2. The memorial foundation of manufacturer Vilhelm Pedersen and wife
  3. Aarhus Wilson consortium
  4. China Scholarship Council
  5. Carl Tryggers foundation [CTS 17:22]
  6. Swedish Research Council [2016-03610]
  7. Swedish National Infrastructure for Computing (SNIC) through the High-Performance Computing Center North (HPC2N) [SNIC 2018/2-32, SNIC 2019/2-29]
  8. Wellcome Trust [209407/Z/17/Z]
  9. Lundbeck
  10. Knut and Alice Wallenberg
  11. Carlsberg
  12. Novo-Nordisk
  13. Brodrene Hartmann
  14. Agnes og Poul Friis
  15. Augustinus
  16. Crafoord
  17. The Per-Eric and Ulla Schyberg
  18. The Independent Research Fund Denmark
  19. Swedish Research Council
  20. Michaelsen scholarship
  21. Robert A Welch Foundation [AT-1935-20170325, AT-2073-20210327]
  22. National Institute of General Medical Sciences of the National Institutes of Health [R35GM128704]
  23. National Science Foundation [CHE-2045984]
  24. Swedish Heart-Lung Foundation [20200378]
  25. Alfred osterlunds Foundation
  26. Royal Physiographic Society of Lund
  27. Danscatt program of the Danish Council of Independent Research

向作者/读者索取更多资源

This study provides structural insights into PIB-4-ATPases, revealing unique metal transport pathways and identifying two compounds that can kill bacteria. Understanding how these proteins work may lead to the development of plants capable of removing heavy metals from contaminated soils and the discovery of new antibiotic compounds.
eLife digest Heavy metals such as zinc and cobalt are toxic at high levels, yet most organisms need tiny amounts for their cells to work properly. As a result, proteins studded through the cell membrane act as gatekeepers to finetune import and export. These proteins are central to health and disease; their defect can lead to fatal illnesses in humans, and they also help bacteria infect other organisms. Despite their importance, little is known about some of these metal-export proteins. This is particularly the case for PIB-4-ATPases, a subclass found in plants and bacteria and which includes, for example, a metal transporter required for bacteria to cause tuberculosis. Intricate knowledge of the three-dimensional structure of these proteins would help to understand how they select metals, shuttle the compounds in and out of cells, and are controlled by other cellular processes. To reveal this three-dimensional organisation, Gronberg et al. used X-ray diffraction, where high-energy radiation is passed through crystals of protein to reveal the positions of atoms. They focused on a type of PIB-4-ATPases found in bacteria as an example. The work showed that the protein does not contain the metal-binding regions seen in other classes of metal exporters; however, it sports unique features that are crucial for metal transport such as an adapted pathway for the transport of zinc and cobalt across the membrane. In addition, Gronberg et al. tested thousands of compounds to see if they could block the activity of the protein, identifying two that could kill bacteria. This better understanding of how PIB-4-ATPases work could help to engineer plants capable of removing heavy metals from contaminated soils, as well as uncover new compounds to be used as antibiotics. Transition metals, such as zinc, are essential micronutrients in all organisms, but also highly toxic in excessive amounts. Heavy-metal transporting P-type (P-IB) 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 (HMBDs), and provide 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 turnover of P-IB-ATPases is potassium independent, contrasting to many other P-type ATPases. Combined with new inhibitory compounds, our results open up for efforts in for example drug discovery, since PIB-4-ATPases function as virulence factors in many pathogens.

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