Abstract
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.
Highlights
We have investigated the molecular and functional role of β 2 and find that it significantly influences the E1P-E2P equilibrium with any of the α subunits studied
Molecular dynamics (MD) simulations suggest that the transmembrane helices of β 1 and β 2 have different tilt angles, and we propose that the tilt angle of β can influence the relative stability of the Na+ occluded E1P state
We found the highest expression of the β 2 isoform in cerebellum (Fig. 2a), and to further delineate, which cells express β 2, brain slices of adult three months old mice were immunostained
Summary
We have investigated the molecular and functional role of β 2 and find that it significantly influences the E1P-E2P equilibrium with any of the α subunits studied. To determine the molecular mechanism of β ’s functional effect, we constructed chimeras of β 1 and β 2, which pinpointed the transmembrane domain as the main determinant for the observed electrophysiological characteristics. Molecular dynamics (MD) simulations suggest that the transmembrane helices of β 1 and β 2 have different tilt angles, and we propose that the tilt angle of β can influence the relative stability of the Na+ occluded E1P state
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