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Nat Struct Mol Biol. 2014 Jan;21(1):43-8. doi: 10.1038/nsmb.2721. Epub 2013 Dec 8.

Copper-transporting P-type ATPases use a unique ion-release pathway.

Author information

1
1] Department of Physiology and Biophysics, University of California at Irvine, Irvine, California, USA. [2] [3].
2
1] Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. [2] [3].
3
Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
4
Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
5
Department of Physiology and Biophysics, University of California at Irvine, Irvine, California, USA.

Abstract

Heavy metals in cells are typically regulated by PIB-type ATPases. The first structure of the class, a Cu(+)-ATPase from Legionella pneumophila (LpCopA), outlined a copper transport pathway across the membrane, which was inferred to be occluded. Here we show by molecular dynamics simulations that extracellular water solvated the transmembrane (TM) domain, results indicative of a Cu(+)-release pathway. Furthermore, a new LpCopA crystal structure determined at 2.8-Å resolution, trapped in the preceding E2P state, delineated the same passage, and site-directed-mutagenesis activity assays support a functional role for the conduit. The structural similarities between the TM domains of the two conformations suggest that Cu(+)-ATPases couple dephosphorylation and ion extrusion differently than do the well-characterized PII-type ATPases. The ion pathway explains why certain Menkes' and Wilson's disease mutations impair protein function and points to a site for inhibitors targeting pathogens.

PMID:
24317491
PMCID:
PMC3904665
DOI:
10.1038/nsmb.2721
[Indexed for MEDLINE]
Free PMC Article

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