Copper-transporting P-type ATPases use a unique ion-release pathway
(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.
(Less)
- author
- Andersson, Magnus ; Mattle, Daniel ; Sitsel, Oleg ; Klymchuk, Tetyana ; Nielsen, Anna Marie ; Møller, Lisbeth Birk ; White, Stephen H ; Nissen, Poul and Gourdon, Pontus LU
- publishing date
- 2014-01
- type
- Contribution to journal
- 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
-
- pmid:24317491
- 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
- 2024-04-14 10:16:08
@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}},
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.}},
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}},
doi = {{10.1038/nsmb.2721}},
volume = {{21}},
year = {{2014}},
}