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

TY - JOUR

T1 - Neurological disease mutations compromise a γ-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 - 2010/9/2

Y1 - 2010/9/2

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-βound form of the pump revealed an intimate docking of the α-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-βinding sites and the cytoplasm. The γ-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-βound 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 γ-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 Ca2+-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-βound form of the pump revealed an intimate docking of the α-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-βinding sites and the cytoplasm. The γ-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-βound 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 γ-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 Ca2+-ATPase.

UR - http://www.scopus.com/inward/record.url?scp=77956312761&partnerID=8YFLogxK

U2 - 10.1038/nature09309

DO - 10.1038/nature09309

M3 - Journal article

C2 - 20720542

AN - SCOPUS:77956312761

SN - 0028-0836

VL - 467

SP - 99

EP - 102

JO - Nature

JF - Nature

IS - 7311

ER -