Publication Date:
2010-08-20
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poulsen, Hanne -- Khandelia, Himanshu -- Morth, J Preben -- Bublitz, Maike -- Mouritsen, Ole G -- Egebjerg, Jan -- Nissen, Poul -- England -- Nature. 2010 Sep 2;467(7311):99-102. doi: 10.1038/nature09309. Epub 2010 Aug 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉PUMPKIN - Centre for Membrane Pumps in Cells and Disease, Danish National Research Foundation, Department of Molecular Biology, Aarhus University, DK-8000 Aarhus C, Denmark. hp@mb.au.dk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20720542" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Crystallography, X-Ray
;
Humans
;
*Ion Transport
;
Migraine with Aura/genetics/*metabolism
;
Models, Molecular
;
Molecular Dynamics Simulation
;
Oocytes/metabolism
;
Potassium/metabolism
;
Protons
;
Sodium-Potassium-Exchanging ATPase/*chemistry/*metabolism
;
Squalus acanthias/metabolism
;
Sus scrofa/metabolism
;
Xenopus
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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