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

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.

Structural basis of ion uptake in copper-transporting P1B-type ATPases

“…The recovered AfCopA structure exhibits the anticipated P 1B -ATPase architecture 16 – 19 , 26 , including the cytosolic A-, P- and N-domains and a total of eight membrane-spanning helices, MA, MB and M1-M6, clearly separating these molecular pumps from other types of P-type ATPases (Fig. 1a & Supplementary Fig.…”

Genome-Wide Identification and Expression Profiling of Heavy Metal ATPase (HMA) Genes in Peanut: Potential Roles in Heavy Metal Transport

“…The 7qc0.1 is the crystal structure of the P 1B-4 -ATPase (sCoaT) from Sulfitobacter sp. NAS14-1, which was shown to transport metal ions such as Zn 2+ , Cd 2+ , and Co 2+ [ 51 ]. The 7si3.1 and 7xuk.1 represent the cryo-electron microscopy structure of ATP7B, a P-type ATPase that exports cytosolic copper from frogs and humans, respectively [ 52 , 53 ].…”

Plastic recognition and electrogenic uniport translocation of 1st-, 2nd-, and 3rd-row transition and post-transition metals by primary-active transmembrane P1B-2-type ATPase pumps

“…2,4 P 1B -type ATPases transmembrane (M) domain possess a common architecture composed of 8 transmembrane helices (MA, -MB, and M1-6), featuring signature sequences involved in intramembrane substrate recognition, 2,4,5,[21][22][23][24] as also revealed by crystal structures and XAS studies of Cu(I)-pumps, Zn(II)pumps and Zn(II)/Co(II)-pumps. [25][26][27][28][29][30][31][32] P 1B -type ATPases subfamilies feature distinct cargo selectivity and exploit a common topological framework, to catalyze the selective transport of diverse 1 st -, 2 nd -, and 3 rd -row transition and post transition metals. 1 The cargo specicity patterns correlate with conserved amino acid motifs present in transmembrane helices M4, M5 and M6.…”