Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport
(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
- Grønberg, Christina ; Sitsel, Oleg ; Lindahl, Erik ; Gourdon, Pontus LU and Andersson, Magnus
- organization
- publishing date
- 2016-12-06
- 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
- pmid:27926843
- 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
- 2024-04-19 16:03:52
@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 = {{https://lup.lub.lu.se/search/files/25358983/18786483.pdf}},
doi = {{10.1016/j.bpj.2016.10.020}},
volume = {{111}},
year = {{2016}},
}