Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase

Hanne Poulsen, Himanshu Khandelia, J Preben Morth, Maike Bublitz, Ole G Mouritsen, Jan Egebjerg, Poul Nissen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The Na(+)/K(+)-ATPase pumps three sodium ions out of and two potassium ions into the cell for each ATP molecule that is split, thereby generating the chemical and electrical gradients across the plasma membrane that are essential in, for example, signalling, secondary transport and volume regulation in animal cells. Crystal structures of the potassium-bound form of the pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain. Here we show that this element is a key regulator of a previously unrecognized ion pathway. Current models of P-type ATPases operate with a single ion conduit through the pump, but our data suggest an additional pathway in the Na(+)/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least eight mutations in the region that cause severe neurological diseases. This novel model for ion transport by the Na(+)/K(+)-ATPase is established by electrophysiological studies of C-terminal mutations in familial hemiplegic migraine 2 (FHM2) and is further substantiated by molecular dynamics simulations. A similar ion regulation is likely to apply to the H(+)/K(+)-ATPase and the Ca(2+)-ATPase.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind467
Udgave nummer7311
Sider (fra-til)99-102
ISSN0028-0836
DOI
StatusUdgivet - 2010

Fingeraftryk

Ions
Mutation
Potassium
Adenosine Triphosphatases
Protons
Sodium-Potassium-Exchanging ATPase
Molecular Dynamics Simulation
sodium-translocating ATPase
Cell Membrane

Citer dette

Poulsen, H., Khandelia, H., Morth, J. P., Bublitz, M., Mouritsen, O. G., Egebjerg, J., & Nissen, P. (2010). Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase. Nature, 467(7311), 99-102. https://doi.org/10.1038/nature09309
Poulsen, Hanne ; Khandelia, Himanshu ; Morth, J Preben ; Bublitz, Maike ; Mouritsen, Ole G ; Egebjerg, Jan ; Nissen, Poul. / Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase. I: Nature. 2010 ; Bind 467, Nr. 7311. s. 99-102.
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abstract = "The Na(+)/K(+)-ATPase pumps three sodium ions out of and two potassium ions into the cell for each ATP molecule that is split, thereby generating the chemical and electrical gradients across the plasma membrane that are essential in, for example, signalling, secondary transport and volume regulation in animal cells. Crystal structures of the potassium-bound form of the pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain. Here we show that this element is a key regulator of a previously unrecognized ion pathway. Current models of P-type ATPases operate with a single ion conduit through the pump, but our data suggest an additional pathway in the Na(+)/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least eight mutations in the region that cause severe neurological diseases. This novel model for ion transport by the Na(+)/K(+)-ATPase is established by electrophysiological studies of C-terminal mutations in familial hemiplegic migraine 2 (FHM2) and is further substantiated by molecular dynamics simulations. A similar ion regulation is likely to apply to the H(+)/K(+)-ATPase and the Ca(2+)-ATPase.",
author = "Hanne Poulsen and Himanshu Khandelia and Morth, {J Preben} and Maike Bublitz and Mouritsen, {Ole G} and Jan Egebjerg and Poul Nissen",
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Poulsen, H, Khandelia, H, Morth, JP, Bublitz, M, Mouritsen, OG, Egebjerg, J & Nissen, P 2010, 'Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase', Nature, bind 467, nr. 7311, s. 99-102. https://doi.org/10.1038/nature09309

Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase. / Poulsen, Hanne; Khandelia, Himanshu; Morth, J Preben; Bublitz, Maike; Mouritsen, Ole G; Egebjerg, Jan; Nissen, Poul.

I: Nature, Bind 467, Nr. 7311, 2010, s. 99-102.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase

AU - Poulsen, Hanne

AU - Khandelia, Himanshu

AU - Morth, J Preben

AU - Bublitz, Maike

AU - Mouritsen, Ole G

AU - Egebjerg, Jan

AU - Nissen, Poul

PY - 2010

Y1 - 2010

N2 - The Na(+)/K(+)-ATPase pumps three sodium ions out of and two potassium ions into the cell for each ATP molecule that is split, thereby generating the chemical and electrical gradients across the plasma membrane that are essential in, for example, signalling, secondary transport and volume regulation in animal cells. Crystal structures of the potassium-bound form of the pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain. Here we show that this element is a key regulator of a previously unrecognized ion pathway. Current models of P-type ATPases operate with a single ion conduit through the pump, but our data suggest an additional pathway in the Na(+)/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least eight mutations in the region that cause severe neurological diseases. This novel model for ion transport by the Na(+)/K(+)-ATPase is established by electrophysiological studies of C-terminal mutations in familial hemiplegic migraine 2 (FHM2) and is further substantiated by molecular dynamics simulations. A similar ion regulation is likely to apply to the H(+)/K(+)-ATPase and the Ca(2+)-ATPase.

AB - The Na(+)/K(+)-ATPase pumps three sodium ions out of and two potassium ions into the cell for each ATP molecule that is split, thereby generating the chemical and electrical gradients across the plasma membrane that are essential in, for example, signalling, secondary transport and volume regulation in animal cells. Crystal structures of the potassium-bound form of the pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain. Here we show that this element is a key regulator of a previously unrecognized ion pathway. Current models of P-type ATPases operate with a single ion conduit through the pump, but our data suggest an additional pathway in the Na(+)/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least eight mutations in the region that cause severe neurological diseases. This novel model for ion transport by the Na(+)/K(+)-ATPase is established by electrophysiological studies of C-terminal mutations in familial hemiplegic migraine 2 (FHM2) and is further substantiated by molecular dynamics simulations. A similar ion regulation is likely to apply to the H(+)/K(+)-ATPase and the Ca(2+)-ATPase.

U2 - 10.1038/nature09309

DO - 10.1038/nature09309

M3 - Journal article

C2 - 20720542

VL - 467

SP - 99

EP - 102

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7311

ER -