Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Sciences, University of Copenhagen, Copenhagen, Denmark
Viktoria Bågenholm
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
Jonas Eriksson
Department of Chemistry, Umeå University, Umeå, Sweden
Komal Umashankar Rao
Department of Laboratory Medicine, Lund University, Lund, Sweden
Domhnall Iain Henderson
Department of Laboratory Medicine, Lund University, Lund, Sweden
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Experimental Medical Science, Lund University, Lund, Sweden
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 (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 PIB-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.
