Structure and mechanism of Zn2+-transporting P-type ATPases

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  • Kaituo Wang, Denmark
  • Oleg Sitsel, Denmark
  • Gabriele Meloni, Denmark
  • Henriette Elisabeth Autzen
  • Magnus Andersson, Science for Life Laboratory, Theoretical and Computational Biophysics, Department of Theoretical Physics, Swedish e-Science Research Center, KTH Royal Institute of Technology, Sweden
  • Tetyana Klymchuk
  • Anna Marie Nielsen
  • Douglas C Rees, Division of Chemistry and Chemical Engineering and Howard Hughes Medical Institute, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA., United States
  • Poul Nissen
  • Pontus Gourdon, Denmark
Zinc is an essential micronutrient for all living organisms. It is required for signalling and proper functioning of a range of proteins involved in, for example, DNA binding and enzymatic catalysis1. In prokaryotes and photosynthetic eukaryotes, Zn2+-transporting P-type ATPases of class IB (ZntA) are crucial for cellular redistribution and detoxification of Zn2+ and related elements2, 3. Here we present crystal structures representing the phosphoenzyme ground state (E2P) and a dephosphorylation intermediate (E2·Pi) of ZntA from Shigella sonnei, determined at 3.2 Å and 2.7 Å resolution, respectively. The structures reveal a similar fold to Cu+-ATPases, with an amphipathic helix at the membrane interface. A conserved electronegative funnel connects this region to the intramembranous high-affinity ion-binding site and may promote specific uptake of cellular Zn2+ ions by the transporter. The E2P structure displays a wide extracellular release pathway reaching the invariant residues at the high-affinity site, including C392, C394 and D714. The pathway closes in the E2·Pi state, in which D714 interacts with the conserved residue K693, which possibly stimulates Zn2+ release as a built-in counter ion, as has been proposed for H+-ATPases. Indeed, transport studies in liposomes provide experimental support for ZntA activity without counter transport. These findings suggest a mechanistic link between PIB-type Zn2+-ATPases and PIII-type H+-ATPases and at the same time show structural features of the extracellular release pathway that resemble PII-type ATPases such as the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase4, 5 (SERCA) and Na+, K+-ATPase6. These findings considerably increase our understanding of zinc transport in cells and represent new possibilities for biotechnology and biomedicine.
Original languageEnglish
JournalNature
Volume514
Issue7523
Pages (from-to)518-522
Number of pages5
ISSN0028-0836
DOIs
Publication statusPublished - 23 Oct 2014

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