Structure and ion-release mechanism of PIB-4-type ATPases
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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 Page 2 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.
|Udgivet - dec. 2021
CG is currently paid by The BRIDGE - Translational Excellence Programme at University of Copenhagen funded by the Novo Nordisk Foundation (NNF18SA0034956). The PhD studies of CG were partly financed by “The memorial foundation of manufacturer Vilhelm Pedersen and wife – and the Aarhus Wilson consortium”. QH was supported by China Scholarship Council. DRM was funded by Carl Tryggers foundation (CTS 17:22), MA was funded by a Swedish Research Council Starting Grant (2016-03610). The computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) through the High-Performance Computing Center North (HPC2N) under project SNIC 2018/2-32 and SNIC 2019/2-29. This research was also funded in part by the Wellcome Trust [209407/Z/17/Z] to TC. PG is supported by the following Foundations: Lundbeck, Knut and Alice Wallenberg, Carlsberg, Novo-Nordisk, Brødrene Hartmann, Agnes og Poul Friis, Augustinus, Crafoord as well as The Per-Eric and Ulla Schyberg. Funding is also obtained from The Independent Research Fund Denmark, the Swedish Research Council and through a Michaelsen scholarship. GM is supported by the Robert A. Welch Foundation (AT-1935-20170325 and AT-2073-20210327), the National Institute of General Medical Sciences of the National Institutes of Health (R35GM128704) and the National Science Foundation (CHE-2045984). GG is funded by the Swedish Heart-Lung Foundation (20200378), Alfred Österlunds Foundation, Royal Physiographic Society of Lund. We are grateful for assistance with
crystal screening at PETRA III at DESY, a member of the Helmholtz Association (HGF), beamline P13, and crystal screening and data collection at the Swiss Light Source, the Paul Scherrer Institute, Villigen, beam line X06SA. Access to synchrotron sources was supported by the Danscatt program of the Danish Council of Independent Research. We acknowledge the Chemical Biology Consortium Sweden (CBCS) at Umeå University that performed the ligand screening. For the purpose of Open Access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission.
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