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Review
.2017 Jun 6:8:371.
doi: 10.3389/fphys.2017.00371. eCollection 2017.

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

Affiliations
Review

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

Michael V Clausen et al. Front Physiol..

Abstract

The sodium and potassium gradients across the plasma membrane are used by animal cells for numerous processes, and the range of demands requires that the responsible ion pump, the Na,K-ATPase, can be fine-tuned to the different cellular needs. Therefore, several isoforms are expressed of each of the three subunits that make a Na,K-ATPase, the alpha, beta and FXYD subunits. This review summarizes the various roles and expression patterns of the Na,K-ATPase subunit isoforms and maps the sequence variations to compare the differences structurally. Mutations in the Na,K-ATPase genes encoding alpha subunit isoforms have severe physiological consequences, causing very distinct, often neurological diseases. The differences in the pathophysiological effects of mutations further underline how the kinetic parameters, regulation and proteomic interactions of the Na,K-ATPase isoforms are optimized for the individual cellular needs.

Keywords: K-ATPase; Na; disease; expression; isoforms; structure; subunits.

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Figures

Figure 1
Figure 1
The structure of the sodium pump. Surface representation of the digoxin bound alpha1 isoform structure from pig (Laursen et al., 2015) (PDB ID: 4RET). Sodium pump subunits and domains are shown in colors as indicated. The two beta glycosylations, digoxin, two cholesterols and the phosphorylated aspartate (D369) are shown as sticks.
Figure 2
Figure 2
Conformational changes during the sodium pump catalytic cycle. Three sodium pump structures and a homology model are positioned in accordance with the catalytic cycle shown below as both cartoon and reaction scheme. The eight inserts labeled with small letters highlight important structural details. The homology model of pig alpha1 on the SERCA E1-ATP state (Winther et al., 2013) (PDB ID: 4H1W) shows an inwardly opened conformation with access to the ion-binding sites, here visualized by D804 and E327(a). In the structure, only the beta and gamma phosphates of the non-hydrolysable ATP analog AMPPCP are resolved and demonstrate a non-primed positioning for reaction with D369(b). After binding of three sodium ions, TM1 rearranges to a position that blocks the cytoplasmic entrance pathway (arrow inc), and the cytoplasmic domains tighten around the nucleotide that reacts with D369(d). Following sodium occlusion ADP is released and an extracellular pathway allows the exit of the three sodium ions. In the externally opened conformation, here imitated by the ouabain bound structure 4HYT shown without the inhibitor, three ion-binding residues are directly visible from the outside(e), and the intracellular domains are completely wrapped around the phosphorylated D369(f). Binding of two extracellular potassium ions(g) initiates closure of the extracellular gate and dephosphorylation of D369(h). The narrow pathway from the cytoplasm to the sodium specific binding site in the cartoon representation shows the proposed C-terminal proton path utilized for charge conservation. Color coding as in Figure 1.
Figure 3
Figure 3
Homology models of the four human alpha isoforms. Models were built from the potassium occluded 3KDP structure (Morth et al., 2007), and the isoform differences are highlighted as spheres. Conservative differences are not included which means that the following groups of amino acids were treated as identical (L, I, V), (E, D), (K, R), (Q, N), (S, T), (Y, F), and (M, C) while H, G, P, A, and W were ungrouped.
Figure 4
Figure 4
Structural maps of the disease-causing mutations. The amino acids altered by disease-causing mutations in the three alpha subunit genes are shown as spheres and color-coded as indicated for each subunit.ATP1A2 andATP1A3 mutations that affect similar positions in the two alphas are also indicated. The alpha1 amino acid alterations have not been reported in the other alphas. The residues are mapped on the potassium-occluded pig kidney structure 2ZXE (Shinoda et al., 2009) (alpha in black cartoon, beta in blue cartoon, gamma in purple cartoon, potassium ions as red spheres). In alpha1, all deleted residues are indicated. In alpha2 and 3, only cases with deletion of single residues are indicated. Under each subunit, it is schematically indicated which loops and TM helices are targeted by mutations. Multiple mutations affecting residues in a single segment are indicated by one mark if they cause the same disease. The mutations are listed underneath using the same color coding, fs: frameshift.
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