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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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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. / Poulsen, Hanne; Nissen, Poul; Mouritsen, Ole G.; Khandelia, Himanshu.

In: Journal of Biological Chemistry, Vol. 287, No. 19, 04.05.2012, p. 15959-15965.

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@article{cf4af97925214d4badec552cbe34d6fb,
title = "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",
abstract = "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.",
keywords = "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",
author = "Hanne Poulsen and Poul Nissen and Mouritsen, {Ole G.} and Himanshu Khandelia",
year = "2012",
month = may,
day = "4",
doi = "10.1074/jbc.M112.340406",
language = "English",
volume = "287",
pages = "15959--15965",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "19",

}

RIS

TY - JOUR

T1 - 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

AU - Poulsen, Hanne

AU - Nissen, Poul

AU - Mouritsen, Ole G.

AU - Khandelia, Himanshu

PY - 2012/5/4

Y1 - 2012/5/4

N2 - 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.

AB - 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.

KW - Animals

KW - Binding Sites

KW - Cyclic AMP-Dependent Protein Kinases

KW - Female

KW - Humans

KW - Hydrogen Bonding

KW - Models, Molecular

KW - Molecular Dynamics Simulation

KW - Mutation

KW - Phosphorylation

KW - Protein Structure, Secondary

KW - Protein Structure, Tertiary

KW - Protein Subunits

KW - Sodium

KW - Sodium-Potassium-Exchanging ATPase

KW - Swine

KW - Water

KW - Xenopus laevis

U2 - 10.1074/jbc.M112.340406

DO - 10.1074/jbc.M112.340406

M3 - Journal article

C2 - 22433860

VL - 287

SP - 15959

EP - 15965

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 19

ER -