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Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity
KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics.
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2017 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 30, p. 12412-12423Article in journal (Refereed) Published
Abstract [en]

Na+/K+-ATPase transports Na+ and K+ ions across the cell membrane via an ion-binding site becoming alternatively accessible to the intra- and extracellular milieu by conformational transitions that confer marked changes in ion-binding stoichiometry and selectivity. To probe the mechanism of these changes, we used molecular simulation and free-energy perturbation approaches to identify probable protonation states of Na+- and K+-coordinating residues in E1P and E2P conformations of Na+/K+-ATPase. Analysis of these simulations revealed a molecular mechanism responsible for the change in protonation state: the conformation-dependent binding of an anion (a chloride ion in our simulations) to a previously unrecognized cytoplasmic site in the loop between transmembrane helices 8 and 9, which influences the electrostatic potential of the crucial Na+-coordinating residue Asp(926). This mechanistic model is consistent with experimental observations and provides a molecular-level picture of how E1P to E2P enzyme conformational transitions are coupled to changes in ion-binding stoichiometry and selectivity.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2017. Vol. 292, no 30, p. 12412-12423
Keyword [en]
membrane transport, molecular dynamics, Na+, K+-ATPase, potassium transport, sodium transport, anion binding site, free energy perturbation, membrane transporter, protonation, selectivity
National Category
Biophysics
Identifiers
URN: urn:nbn:se:kth:diva-212622DOI: 10.1074/jbc.M117.779090ISI: 000406636900007Scopus ID: 2-s2.0-85026287956OAI: oai:DiVA.org:kth-212622DiVA, id: diva2:1136067
Funder
EU, FP7, Seventh Framework Programme, PIOF-GA-2012-329534
Note

QC 20170825

Available from: 2017-08-25 Created: 2017-08-25 Last updated: 2017-08-25Bibliographically approved

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  • apa
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