Structural and functional insights into a Zn²⁺-transporting P-type ATPase.
7 affiliations
- 1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
- 2Department of Chemistry, Umeå University, Umeå, Sweden.
- 3Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA.
- 4Department of Experimental Medical Science, Lund University, Lund, Sweden.
- 5Department of Haematology, University of Cambridge, Cambridge, UK.
- 6Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].
- 7Department of Experimental Medical Science, Lund University, Lund, Sweden. [email protected].
Abstract
Zinc is essential for life yet toxic in excess, rendering homeostatic control vital for all organisms. Transition metal transporting P-type (PIB-) ATPase proteins are critical for this balance but remain poorly understood at the molecular level. Here, we present the inward-open structure of a dimeric zinc-transporting PIB-type ATPase, resolved at 3.6 Å resolution. Biochemical analyses and molecular dynamics simulations suggest that the N-terminal tail, harboring two so-called metal binding domains (MBDs), auto-inhibits the ATPase core and serves as a metal-sensitive sensor, releasing inhibition when intracellular metal levels rise. Contrary to the prevailing uptake models, the structure reveals an electronegatively charged uptake region that directly exposes a metal-binding cysteine of the invariant CPC-motif. We propose that a histidine-rich segment, positioned after the MBD closest to the core, donates ions to the CPC site. Consequently, an intricate interplay between the regulatory and ion-providing N-terminus and the ATPase core is present, safeguarding against zinc toxicity. Collectively, our findings shed light on the regulation and transport mechanism of PIB-ATPases, with implications for fundamental biology and the potential to inform future biotechnological and translational applications.
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BibTeX
@article{lyu2026structural,
title = {{Structural and functional insights into a Zn²⁺-transporting P-type ATPase.}},
author = {Pin Lyu and Elena Longhin and Fatemeh Sabzian-Molaei and Fernando Montalvillo Ortega and Ping Li and Kaituo Wang and Annette Duelli and Tamim Al-Jubair and Hajira Ahmed Hotiana and Eva Ramos Becares and Tristan Croll and Gabriele Meloni and Magnus Andersson and Viktoria Bågenholm and Pontus Gourdon},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77558-1},
url = {https://europepmc.org/article/MED/42894012},
note = {CC BY},
}
RIS
TY - JOUR
TI - Structural and functional insights into a Zn²⁺-transporting P-type ATPase.
AU - Pin Lyu
AU - Elena Longhin
AU - Fatemeh Sabzian-Molaei
AU - Fernando Montalvillo Ortega
AU - Ping Li
AU - Kaituo Wang
AU - Annette Duelli
AU - Tamim Al-Jubair
AU - Hajira Ahmed Hotiana
AU - Eva Ramos Becares
AU - Tristan Croll
AU - Gabriele Meloni
AU - Magnus Andersson
AU - Viktoria Bågenholm
AU - Pontus Gourdon
PY - 2026
DA - 2026/09/16
JO - Nature communications
DO - 10.1038/s41467-026-77558-1
UR - https://europepmc.org/article/MED/42894012
AB - Zinc is essential for life yet toxic in excess, rendering homeostatic control vital for all organisms. Transition metal transporting P-type (PIB-) ATPase proteins are critical for this balance but remain poorly understood at the molecular level. Here, we present the inward-open structure of a dimeric zinc-transporting PIB-type ATPase, resolved at 3.6 Å resolution. Biochemical analyses and molecular dynamics simulations suggest that the N-terminal tail, harboring two so-called metal binding domains (MBDs), auto-inhibits the ATPase core and serves as a metal-sensitive sensor, releasing inhibition when intracellular metal levels rise. Contrary to the prevailing uptake models, the structure reveals an electronegatively charged uptake region that directly exposes a metal-binding cysteine of the invariant CPC-motif. We propose that a histidine-rich segment, positioned after the MBD closest to the core, donates ions to the CPC site. Consequently, an intricate interplay between the regulatory and ion-providing N-terminus and the ATPase core is present, safeguarding against zinc toxicity. Collectively, our findings shed light on the regulation and transport mechanism of PIB-ATPases, with implications for fundamental biology and the potential to inform future biotechnological and translational applications.
SN - 2041-1723
ER -