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Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport

Grønberg, Christina; Sitsel, Oleg; Lindahl, Erik; Gourdon, Pontus LU and Andersson, Magnus (2016) In Biophysical Journal 111(11). p.2417-2429
Abstract

Cu+-specific P-type ATPase membrane protein transporters regulate cellular copper levels. The lack of crystal structures in Cu+-binding states has limited our understanding of how ion entry and binding are achieved. Here, we characterize the molecular basis of Cu+ entry using molecular-dynamics simulations, structural modeling, and in vitro and in vivo functional assays. Protein structural rearrangements resulting in the exposure of positive charges to bulk solvent rather than to lipid phosphates indicate a direct molecular role of the putative docking platform in Cu+ delivery. Mutational analyses and simulations in the presence and absence of Cu+ predict that the ion-entry path... (More)

Cu+-specific P-type ATPase membrane protein transporters regulate cellular copper levels. The lack of crystal structures in Cu+-binding states has limited our understanding of how ion entry and binding are achieved. Here, we characterize the molecular basis of Cu+ entry using molecular-dynamics simulations, structural modeling, and in vitro and in vivo functional assays. Protein structural rearrangements resulting in the exposure of positive charges to bulk solvent rather than to lipid phosphates indicate a direct molecular role of the putative docking platform in Cu+ delivery. Mutational analyses and simulations in the presence and absence of Cu+ predict that the ion-entry path involves two ion-binding sites: one transient Met148-Cys382 site and one intramembranous site formed by trigonal coordination to Cys384, Asn689, and Met717. The results reconcile earlier biochemical and x-ray absorption data and provide a molecular understanding of ion entry in Cu+-transporting P-type ATPases.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biophysical Journal
volume
111
issue
11
pages
13 pages
publisher
Cell Press
external identifiers
  • scopus:85002251320
  • wos:000389563900011
ISSN
0006-3495
DOI
10.1016/j.bpj.2016.10.020
language
English
LU publication?
yes
id
99a3c10b-a746-4b1d-a87b-9a2668d68ca2
date added to LUP
2016-12-28 08:26:45
date last changed
2017-09-18 11:33:24
@article{99a3c10b-a746-4b1d-a87b-9a2668d68ca2,
  abstract     = {<p>Cu<sup>+</sup>-specific P-type ATPase membrane protein transporters regulate cellular copper levels. The lack of crystal structures in Cu<sup>+</sup>-binding states has limited our understanding of how ion entry and binding are achieved. Here, we characterize the molecular basis of Cu<sup>+</sup> entry using molecular-dynamics simulations, structural modeling, and in vitro and in vivo functional assays. Protein structural rearrangements resulting in the exposure of positive charges to bulk solvent rather than to lipid phosphates indicate a direct molecular role of the putative docking platform in Cu<sup>+</sup> delivery. Mutational analyses and simulations in the presence and absence of Cu<sup>+</sup> predict that the ion-entry path involves two ion-binding sites: one transient Met148-Cys382 site and one intramembranous site formed by trigonal coordination to Cys384, Asn689, and Met717. The results reconcile earlier biochemical and x-ray absorption data and provide a molecular understanding of ion entry in Cu<sup>+</sup>-transporting P-type ATPases.</p>},
  author       = {Grønberg, Christina and Sitsel, Oleg and Lindahl, Erik and Gourdon, Pontus and Andersson, Magnus},
  issn         = {0006-3495},
  language     = {eng},
  month        = {12},
  number       = {11},
  pages        = {2417--2429},
  publisher    = {Cell Press},
  series       = {Biophysical Journal},
  title        = {Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport},
  url          = {http://dx.doi.org/10.1016/j.bpj.2016.10.020},
  volume       = {111},
  year         = {2016},
}