The selectivity of the Na+/K+-pump is controlled by binding site protonation and self-correcting occlusion

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Abstract

The Na⁺/K⁺-pump maintains the physiological K⁺ and Na⁺ electrochemical gradients across the cell membrane. It operates via an 'alternating-access' mechanism, making iterative transitions between inward-facing (E₁) and outward-facing (E₂) conformations. Although the general features of the transport cycle are known, the detailed physicochemical factors governing the binding site selectivity remain mysterious. Free energy molecular dynamics simulations show that the ion binding sites switch their binding specificity in E₁ and E₂. This is accompanied by small structural arrangements and changes in protonation states of the coordinating residues. Additional computations on structural models of the intermediate states along the conformational transition pathway reveal that the free energy barrier toward the occlusion step is considerably increased when the wrong type of ion is loaded into the binding pocket, prohibiting the pump cycle from proceeding forward. This self-correcting mechanism strengthens the overall transport selectivity and protects the stoichiometry of the pump cycle.

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Huan Rui

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6459-9871
Pablo Artigas

Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, United States

Competing interests
The authors declare that no competing interests exist.
Benoît Roux

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States

For correspondence
roux@uchicago.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5254-2712

Funding

National Institutes of Health (U54-GM087519)

Benoît Roux

National Science Foundation (MCB-1515434)

Pablo Artigas

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.