Structure and ion-release mechanism of PIB-4-type ATPases.
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.
Funder: The memorial foundation of manufacturer Vilhelm Pedersen and wife - and the Aarhus Wilson consortium
Funder: China Scholarship Council; FundRef: http://dx.doi.org/10.13039/501100004543
Funder: Carl Tryggers Stiftelse för Vetenskaplig Forskning; FundRef: http://dx.doi.org/10.13039/501100002805; Grant(s): CTS 17:22
Funder: Agnes og Poul Friis Fond; FundRef: http://dx.doi.org/10.13039/100009512