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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

DOI

  • Magnus Andersson, Department of Physiology and Biophysics, University of California at Irvine, Irvine, California, USA.
    • ,
  • Daniel Mattle, Danmark
  • Oleg Sitsel, Danmark
  • Tetyana Klymchuk, Danmark
  • Anna Marie Nielsen
  • Lisbeth Birk Møller, SUND ph.d. skole, Danmark
  • Stephen H White, Department of Physiology and Biophysics, University of California at Irvine, Irvine, California, USA.
    • ,
  • Poul Nissen
  • Pontus Gourdon, Danmark
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.
OriginalsprogEngelsk
TidsskriftNature Structural and Molecular Biology
Vol/bind21
Sider (fra-til)43-48
Antal sider6
ISSN1545-9993
DOI
StatusUdgivet - 2014

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