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Protein kinase A (PKA) phosphorylation of Na+/K+-ATPase opens intracellular C-terminal water pathway leading to third Na+-binding site in molecular dynamics simulations

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  • Hanne Poulsen
  • Poul Nissen
  • Ole G. Mouritsen, MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark, Denmark
  • Himanshu Khandelia, MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark, Denmark
Phosphorylation is one of the major mechanisms for posttranscriptional modification of proteins. The addition of a compact, negatively charged moiety to a protein can significantly change its function and localization by affecting its structure and interaction network. We have used all-atom Molecular Dynamics simulations to investigate the structural consequences of phosphorylating the Na(+)/K(+)-ATPase (NKA) residue Ser(936), which is the best characterized phosphorylation site in NKA, targeted in vivo by protein kinase A (PKA). The Molecular Dynamics simulations suggest that Ser(936) phosphorylation opens a C-terminal hydrated pathway leading to Asp(926), a transmembrane residue proposed to form part of the third sodium ion-binding site. Simulations of a S936E mutant form, for which only subtle effects are observed when expressed in Xenopus oocytes and studied with electrophysiology, does not mimic the effects of Ser(936) phosphorylation. The results establish a structural association of Ser(936) with the C terminus of NKA and indicate that phosphorylation of Ser(936) can modulate pumping activity by changing the accessibility to the ion-binding site.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume287
Issue19
Pages (from-to)15959-15965
Number of pages7
ISSN0021-9258
DOIs
Publication statusPublished - 4 May 2012

    Research areas

  • Animals, Binding Sites, Cyclic AMP-Dependent Protein Kinases, Female, Humans, Hydrogen Bonding, Models, Molecular, Molecular Dynamics Simulation, Mutation, Phosphorylation, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Subunits, Sodium, Sodium-Potassium-Exchanging ATPase, Swine, Water, Xenopus laevis

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