K+ Congeners That Do Not Compromise Na+ Activation of the Na+,K+-ATPase

Mahmmoud, Yasser A.; Kopeć, Wojciech; Khandelia, Himanshu

doi:10.1074/jbc.m114.577486

Cited by 9 publications

(4 citation statements)

References 61 publications

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“…All-atom MD simulations were performed in a manner similar to one described in a recent publication 52 . The recently determined, crystal structure of the [Na 3 ] E1-AlF4-ADP form of pig kidney NaKA (PDB ID: 3WGU 4 ) was used as a starting point of the simulations.…”

Section: Methodsmentioning

confidence: 99%

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Tuning of the Na,K-ATPase by the beta subunit

Hilbers

Kopeć

Isaksen

et al. 2016

Sci Rep

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The vital gradients of Na+ and K+ across the plasma membrane of animal cells are maintained by the Na,K-ATPase, an αβ enzyme complex, whose α subunit carries out the ion transport and ATP hydrolysis. The specific roles of the β subunit isoforms are less clear, though β2 is essential for motor physiology in mammals. Here, we show that compared to β1 and β3, β2 stabilizes the Na+-occluded E1P state relative to the outward-open E2P state, and that the effect is mediated by its transmembrane domain. Molecular dynamics simulations further demonstrate that the tilt angle of the β transmembrane helix correlates with its functional effect, suggesting that the relative orientation of β modulates ion binding at the α subunit. β2 is primarily expressed in granule neurons and glomeruli in the cerebellum, and we propose that its unique functional characteristics are important to respond appropriately to the cerebellar Na+ and K+ gradients.

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Section: Methodsmentioning

confidence: 99%

“…System construction – The Na + coordinating residues E327 and E779 at binding sites I and II , as well as E954 at the unoccupied site IIIa were kept protonated 52 . The remaining glutamate and aspartate residues were kept in the charged state.…”

Section: Methodsmentioning

confidence: 99%

Tuning of the Na,K-ATPase by the beta subunit

Hilbers

Kopeć

Isaksen

et al. 2016

Sci Rep

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“…More than 40% of the energy produced in mammals is consumed by the Na + /K + -pump ( Milligan et al, 1985 ). Although it is a machine designed for such a precise and important function, it has been shown that many cations, including congeners of K + and some organic cations, can bind to the same sites used by the pump to bind and transport K + ions ( Mahmmoud et al, 2015 ; Ratheal et al, 2010 ). Competitive binding between Na + and other cations at the cytoplasmic side of the membrane has also been observed ( Schneeberger et al, 2001 ).…”

Section: Introductionmentioning

confidence: 99%

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

Rui

Artigas

Roux

2016

eLife

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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.DOI: http://dx.doi.org/10.7554/eLife.16616.001

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“…Since too many water molecules inside the binding pocket can cause the hydration and destabilization of Na + ions1252, we consider a state with fewer waters around the bound Na + ions as a more stable one. Note that at least two water molecules accompany Na + in all simulations.…”

Section: Resultsmentioning

confidence: 99%

Glutamate Water Gates in the Ion Binding Pocket of Na+ Bound Na+, K+-ATPase

Han

Kopeć

Solov’yov

et al. 2017

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The dynamically changing protonation states of the six acidic amino acid residues in the ion binding pocket of the Na+, K+ -ATPase (NKA) during the ion transport cycle are proposed to drive ion binding, release and possibly determine Na+ or K+ selectivity. We use molecular dynamics (MD) and density functional theory (DFT) simulations to determine the protonation scheme of the Na+ bound conformation of NKA. MD simulations of all possible protonation schemes show that the bound Na+ ions are most stably bound when three or four protons reside in the binding sites, and that Glu954 in site III is always protonated. Glutamic acid residues in the three binding sites act as water gates, and their deprotonation triggers water entry to the binding sites. From DFT calculations of Na+ binding energies, we conclude that three protons in the binding site are needed to effectively bind Na+ from water and four are needed to release them in the next step. Protonation of Asp926 in site III will induce Na+ release, and Glu327, Glu954 and Glu779 are all likely to be protonated in the Na+ bound occluded conformation. Our data provides key insights into the role of protons in the Na+ binding and release mechanism of NKA.

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K+ Congeners That Do Not Compromise Na+ Activation of the Na+,K+-ATPase

Abstract: Background:The Na ϩ ,K ϩ -ATPase discriminates between similar and abundant ions.

Cited by 9 publications

References 61 publications

Tuning of the Na,K-ATPase by the beta subunit

Tuning of the Na,K-ATPase by the beta subunit

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

Glutamate Water Gates in the Ion Binding Pocket of Na+ Bound Na+, K+-ATPase

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