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

Gronberg, C.; Hu, Q.; Mahato, D. R.; Longhin, E.; Salustros, N.; Duelli, A.; Eriksson, J.; Rao, K. U.; Henderson, D. I.; Meloni, G.; Andersson, M.; Croll, T.; Godaly, G.; Wang, K.; Gourdon, P.

doi:10.1101/2021.09.01.458532

bioRxiv · 10.1101/2021.09.01.458532

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

Gronberg, C.·Hu, Q.·Mahato, D. R.·Longhin, E.·Salustros, N.·Duelli, A.·Eriksson, J.·Rao, K. U.·Henderson, D. I.·Meloni, G.·Andersson, M.·Croll, T.·Godaly, G.·Wang, K.·Gourdon, P.

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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-ATPases, 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, central 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.

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Gronberg, C., Hu, Q., Mahato, D. R., Longhin, E., Salustros, N., Duelli, A., Eriksson, J., Rao, K. U., Henderson, D. I., Meloni, G., Andersson, M., Croll, T., Godaly, G., Wang, K., Gourdon, P.. 2021-09-05. Structure and ion-release mechanism of PIB-4-type ATPases. https://doi.org/10.1101/2021.09.01.458532

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