期刊
NATURE
卷 514, 期 7523, 页码 518-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13618
关键词
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资金
- Graduate School of Science and Technology at Aarhus University
- Marie Curie International Outgoing Fellowship (European Commission) [252961]
- Marie Curie Career Integration Grant [FP7-MC-CIG-618558]
- European Research Council [250322 Biomemos]
- Lundbeck Foundation
- Swedish Research Council [K2013-99X-22251-01-5]
- Danscatt program of the Danish Council of Independent Research
- BioStruct-X [860]
- Lundbeck Foundation [R139-2012-12689] Funding Source: researchfish
- Novo Nordisk Fonden [NNF12OC0002082] Funding Source: researchfish
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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