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Structure and mechanism of Zn2+-transporting P-type ATPases
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2014 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 514, no 7523, 518-+ p.Article in journal (Refereed) Published
Abstract [en]

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 catalysis(1). 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 elements(2,3). Here we present crystal structures representing the phosphoenzyme ground state (E2P) and a dephosphorylation intermediate (E2.P-i) of ZntA from Shigella sonnei, determined at 3.2 angstrom and 2.7 angstrom 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.P-i 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 P-IB-type Zn2+-ATPases and P-III-type H+-ATPases and at the same time show structural features of the extracellular release pathway that resemble P-II-type ATPases such as the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase(4,5) (SERCA) and Na+, K+-ATPase(6). These findings considerably increase our understanding of zinc transport in cells and represent new possibilities for biotechnology and biomedicine.

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2014. Vol. 514, no 7523, 518-+ p.
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URN: urn:nbn:se:kth:diva-156441DOI: 10.1038/nature13618ISI: 000343775900046OAI: diva2:767986

QC 20141202

Available from: 2014-12-02 Created: 2014-11-28 Last updated: 2014-12-02Bibliographically approved

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Andersson, Magnus
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Theoretical & Computational BiophysicsScience for Life Laboratory, SciLifeLab
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