Affiliation:
1. Department of Biomedical Sciences, University of Copenhagen
2. Department of Chemistry, Umeå University
3. Department of Laboratory Medicine, Lund University
4. Department of Chemistry and Biochemistry, The University of Texas at Dallas
5. Department of Haematology, University of Cambridge
6. Department of Laboratory Medicine, Umeå University
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.
Funder
Novo Nordisk Fonden
Lundbeckfonden
Knut och Alice Wallenbergs Stiftelse
Carlsbergfondet
Brodrene Hartmann
Agnes og Poul Friis Fond
Augustinus Fonden
Crafoord
Per-Eric and Ulla Schyberg
Swedish Research Council
The memorial foundation of manufacturer Vilhelm Pedersen and wife - and the Aarhus Wilson consortium
The Independent Research Fund Denmark
China Scholarship Council
Carl Tryggers Stiftelse för Vetenskaplig Forskning
Swedish Research Council Starting Grant
Robert A. Welke Cancer Research Foundation
National Institute of General Medical Sciences
National Science Foundation
Swedish Heart-Lung Foundation
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
6 articles.
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