The Quaternary Structure of the Sodium Pump Regulatory Complex Is Altered by Mutations of a Site Associated with Familial Hemiplegic Migraine
Abstract
The sodium–potassium ATPase (Na + /K + -ATPase, NKA) is a P-type ATPase that plays a central role in cell physiology, establishing Na + and K + gradients across the plasma membrane. We have previously investigated the assembly of the NKA complex, quantifying interactions of the catalytic subunit, alpha, with its accessory subunit, beta, and a regulatory microprotein from the FXYD family, phospholemman (PLM). We also investigated the dimerization of alpha subunits, together with accessory proteins, in a larger complex with stoichiometry (alpha beta-PLM) 2 . A structural model of the (alpha beta-PLM) 2 dimer complex suggested key interacting surfaces between the highly conserved alpha subunit M3 helix and the N-terminus of the beta subunit in the opposing transporter. This contact was of particular interest as this region of NKA has been implicated in disease. In this study, we focused on mutations of M3 helix residue G301 that have been implicated in renal hypomagnesemia and familial hemiplegic migraine. We used fluorescence spectroscopy, fluorescence microscopy, and molecular dynamics (MD) simulations to investigate the changes in NKA regulatory complex structure after mutation of G301 to alanine or arginine. For both mutants, we observed decreased plasma membrane localization, small alterations in the quaternary conformation of the NKA dimer complex, and decreased affinity of the interactions between protomers. Interestingly, G301A/R mutants showed instability of Na +…
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