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

Andersson, Magnus; Mattle, Daniel; Sitsel, Oleg; Klymchuk, Tetyana; Nielsen, Anna Marie; Møller, Lisbeth Birk; White, Stephen H; Nissen, Poul and Gourdon, Pontus LU (2014) In Nature Structural and Molecular Biology 21(1). p.8-43
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... (More)

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.

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publication status
published
keywords
Adenosine Triphosphatases, Copper, Ions, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Protein Conformation, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
in
Nature Structural and Molecular Biology
volume
21
issue
1
pages
6 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:84893785220
ISSN
1545-9985
DOI
10.1038/nsmb.2721
language
English
LU publication?
no
id
6320cd3e-e281-49fe-bdbb-5c8556a5bd87
date added to LUP
2017-04-29 15:29:18
date last changed
2017-10-01 05:33:43
@article{6320cd3e-e281-49fe-bdbb-5c8556a5bd87,
  abstract     = {<p>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.</p>},
  author       = {Andersson, Magnus and Mattle, Daniel and Sitsel, Oleg and Klymchuk, Tetyana and Nielsen, Anna Marie and Møller, Lisbeth Birk and White, Stephen H and Nissen, Poul and Gourdon, Pontus},
  issn         = {1545-9985},
  keyword      = {Adenosine Triphosphatases,Copper,Ions,Molecular Dynamics Simulation,Mutagenesis, Site-Directed,Protein Conformation,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't,Research Support, U.S. Gov't, Non-P.H.S.},
  language     = {eng},
  number       = {1},
  pages        = {8--43},
  publisher    = {Nature Publishing Group},
  series       = {Nature Structural and Molecular Biology},
  title        = {Copper-transporting P-type ATPases use a unique ion-release pathway},
  url          = {http://dx.doi.org/10.1038/nsmb.2721},
  volume       = {21},
  year         = {2014},
}