Ion Motive ATPases: P‐type ATPases


Regulation of ions such as calcium, sodium and potassium ions is very important for cell life. One of ion‐regulating enzymes is classified as ion motive adenosine triphosphatase (ATPase). Ion motive ATPases exchange two different ions across the membrane at the expense of ATP energy. The Ca2+‐ATPase transports Ca ion in exchange for H ion; the Na+/K+ or H+/K+ATPase transports Na ion or hydronium ion from the cytoplasmic region to the exocytoplasmic region with the exchange of K ion from the exoplasmic domain to the cytoplasmic domain. The Ca2+‐ATPase has single catalytic subunit. The Na+/K+ and H+/K+ATPases consist of two subunits α and β. The α subunit is the catalytic subunit, having 10 transmembrane domains. The β subunit is a glycosylated protein.

Key concepts

  • Ion motive ATPases

  • P‐type ATPase transport ions across the membrane

  • Regulating ion concentrations.

Keywords: pumps; ATPase; P‐type

Figure 1.

The various types of eukaryotic P2‐ATPases. The electrogenic yeast H+‐ATPase, the Ca2+‐ATPase, the Na+/K+‐ATPase and gastric H+/K+‐ATPase are illustrated. Among these ATPases, only the gastric H+/K+‐ATPase is electroneutral.

Figure 2.

The reaction steps of a typical countertransport P2‐ATPase such as the gastric H+/K+‐ATPase. The reaction starts (top centre) by binding of the primary transport cation. This is followed by phosphorylation, occlusion (centre of figure) and change of sidedness of the binding site. After release of the initial cation, the countertransport cation is bound, the enzyme dephosphorylates and the counter‐ion moves to the other side of the enzyme.

Figure 3.

SERCA1a structures representing key states of the reaction cycle. Cation‐ and nucleotide‐exchange reactions are indicated. The structures are depicted by grey, transparent surfaces and by cartoon representations, with the A‐domain in yellow, N‐domain in red, P‐domain in blue, transmembrane segment M1–M2 in purple, M3–M4 in green, M5–M6 in wheat and M7–M10 in grey. Each model of the structure is based on the work of Olesen et al..

Figure 4.

Structure of the Na+/K+‐ATPase αβγ complex. Cytoplasmic domain consists of N‐, A‐ and P‐domains. In the membrane domain, there are 10 transmembrane segments in the α subunit, 1 transmembrane segment each in the β and γ subunit. Carbohydrates are attached to the β subunit in the extracellular domain. This structure model is based on the work of Morth et al..



Arguello JM, Mandal AK and Mana‐Capelli S (2003) Heavy metal transport CPx‐ATPases from the thermophile Archaeoglobus fulgidus. Annals of the New York Academy of Sciences 986: 212–218.

Askew GR and Lingrel JB (1994) Identification of an amino acid substitution in human alpha 1 Na,K‐ATPase which confers differentially reduced affinity for two related cardiac glycosides. Journal of Biological Chemistry 269: 24120–24126.

Besancon M, Simon A, Sachs G and Shin JM (1997) Sites of reaction of the gastric H,K‐ATPase with extracytoplasmic thiol reagents. Journal of Biological Chemistry 272: 22438–22446.

Bibert S, Roy S, Schaer D, Horisberger JD and Geering K (2008) Phosphorylation of phospholemman (FXYD1) by protein kinases A and C modulates distinct Na,K‐ATPase isozymes. Journal of Biological Chemistry 283: 476–486.

Canessa CM, Horisberger JD and Rossier BC (1993) Mutation of a tyrosine in the H3‐H4 ectodomain of Na,K‐ATPase alpha subunit confers ouabain resistance. Journal of Biological Chemistry 268: 17722–17726.

Cheung JY, Rothblum LI, Moorman JR et al. (2007) Regulation of cardiac Na+/Ca2+ exchanger by phospholemman. Annals of the New York Academy of Sciences 1099: 119–134.

Crambert G, Fuzesi M, Garty H, Karlish S and Geering K (2002) Phospholemman (FXYD1) associates with Na,K‐ATPase and regulates its transport properties. Proceedings of the National Academy of Sciences of the United States of America 99: 11476–11481.

Di Leva F, Domi T, Fedrizzi L, Lim D and Carafoli E (2008) The plasma membrane Ca2+ ATPase of animal cells: structure, function and regulation. Archives of Biochemistry and Biophysics 476: 65–74.

Geering K (2005) Function of FXYD proteins, regulators of Na,K‐ATPase. Journal of Bioenergetics and Biomembrane 37: 387–392.

Geering K (2008) Functional roles of Na,K‐ATPase subunits. Current Opinion in Nephrology and Hypertension 17: 526–532.

Geering K, Beguin P, Garty H et al. (2003) FXYD proteins: new tissue‐ and isoform‐specific regulators of Na,K‐ATPase. Annals of the New York Academy of Sciences 986: 388–394.

Greie J C and Altendorf K (2007) The K+‐translocating KdpFABC complex from E. coli: a P‐type ATPase with unique features. Journal of Bioenergetics and Biomembrane 39: 397–402.

Heitkamp T, Kalinowski R, Bottcher B et al. (2008) K+‐translocating KdpFABC P‐type ATPase from E. coli acts as a functional and structural dimer. Biochemistry 47: 3564–3575.

Kaler SG, Holmes CS, Goldstein DS et al. (2008) Neonatal diagnosis and treatment of Menkes disease. New England Journal of Medicine 358: 605–614.

Khundmiri SJ, Ameen M, Delamere NA and Lederer ED (2008) PTH‐mediated regulation of Na+‐K+‐ATPase requires Src kinase‐dependent ERK phosphorylation. American Journal of Physiology. Renal Physiology 295: F426–F437.

Lambrecht NW, Yakubov I, Scott D and Sachs G (2005) Identification of the K efflux channel coupled to the gastric H‐K‐ATPase during acid secretion. Physiological Genomics 21: 81–91.

Lutsenko S, Barnes NL, Bartee MY and Dmitriev OY (2007) Function and regulation of human copper‐transporting ATPases. Physiological Reviews 87: 1011–1046.

Morth JP, Pedersen BP, Toustrup‐Jensen MS et al. (2007) Crystal structure of the sodium‐potassium pump. Nature 450: 1043–1049.

Munson K, Garcia R and Sachs G (2005) Inhibitor and ion binding sites on the gastric H,K‐ATPase. Biochemistry 44: 5267–5284.

Munson K, Law RJ and Sachs G (2007) Analysis of the gastric H,K ATPase for ion pathways and inhibitor binding sites. Biochemistry 46: 5398–5417.

Olesen C, Picard M, Winther AM et al. (2007) The structural basis of calcium transport by the calcium pump. Nature 450: 1036–1042.

Or E, Goldshleger ED, Tal DM and Karlish SJ (1996) Solubilization of a complex of tryptic fragments of Na,K‐ATPase containing occluded Rb ions and bound ouabain. Biochemistry 35: 6853–6864.

Radkov R, Kharoubi‐Hess S, Schaer D et al. (2007) Role of homologous ASP334 and GLU319 in human non‐gastric H,K‐ and Na,K‐ATPases in cardiac glycoside binding. Biochemical and Biophysical Research Communications 356: 142–146.

Sachs G, Shin JM, Vagin O et al. (2007) The gastric H,K ATPase as a drug target: past, present, and future. Journal of Clinical Gastroenterology 41(suppl. 2): S226–S242.

Schoner W and Scheiner‐Bobis G (2007) Endogenous and exogenous cardiac glycosides and their mechanisms of action. American Journal of Cardiovascular Drugs 7: 173–189.

Shani M, Goldschleger R and Karlish SJ (1987) Rb+ occlusion in renal (Na+ + K+)‐ATPase characterized with a simple manual assay. Biochimica et Biophysica Acta 904: 13–21.

Shin JM, Grundler G, Senn‐Bilfinger J, Simon WA and Sachs G (2005) Functional consequences of the oligomeric form of the membrane‐bound gastric H,K‐ATPase. Biochemistry 44: 16321–16332.

Shin JM, Munson K, Vagin O and Sachs G (2009) The gastric HK‐ATPase: structure, function, and inhibition. Pflügers Archiv – European Journal of Physiology 457: 609–622.

Shin JM and Sachs G (1994) Identification of a region of the H,K‐ATPase alpha subunit associated with the beta subunit. Journal of Biological Chemistry 269: 8642–8646.

Shin JM and Sachs G (1996) Dimerization of the gastric H+, K(+)‐ATPase. Journal of Biological Chemistry 271: 1904–1908.

Shin JM and Sachs G (2008) Pharmacology of proton pump inhibitors. Current Gastroenterology Reports 10: 528–534.

Takahashi M, Kondou Y and Toyoshima C (2007) Interdomain communication in calcium pump as revealed in the crystal structures with transmembrane inhibitors. Proceedings of the National Academy of Sciences of the United States of America 104: 5800–5805.

Toyoshima C, Nakasako M, Nomura H and Ogawa H (2000) Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A resolution. Nature 405: 647–655.

Toyoshima C, Nomura H and Sugita Y (2003a) Crystal structures of Ca2+‐ATPase in various physiological states. Annals of the New York Academy of Sciences 986: 1–8.

Toyoshima C, Nomura H and Sugita Y (2003b) Structural basis of ion pumping by Ca(2+)‐ATPase of sarcoplasmic reticulum. FEBS Letters 555: 106–110.

Toyoshima C, Norimatsu Y, Iwasawa S, Tsuda T and Ogawa H (2007) How processing of aspartylphosphate is coupled to lumenal gating of the ion pathway in the calcium pump. Proceedings of the National Academy of Sciences of the United States of America 104: 19831–19836.

Vagin O, Sachs G and Tokhtaeva E (2007a) The roles of the Na,K‐ATPase beta 1 subunit in pump sorting and epithelial integrity. Journal of Bioenergetics and Biomembrane 39: 367–372.

Vagin O, Tokhtaeva E and Sachs G (2006) The role of the beta1 subunit of the Na,K‐ATPase and its glycosylation in cell‐cell adhesion. Journal of Biological Chemistry 281: 39573–39587.

Vagin O, Tokhtaeva E, Yakubov I, Shevchenko E and Sachs G (2008) Inverse correlation between the extent of N‐glycan branching and intercellular adhesion in epithelia. Contribution of the Na,K‐ATPase beta1 subunit. Journal of Biological Chemistry 283: 2192–2202.

Vagin O, Turdikulova S and Tokhtaeva E (2007b) Polarized membrane distribution of potassium‐dependent ion pumps in epithelial cells: different roles of the N‐glycans of their beta subunits. Cell Biochemistry and Biophysics 47: 376–391.

Vilsen B, Andersen JP, Petersen J and Jorgensen PL (1987) Occlusion of 22Na+ and 86Rb+ in membrane‐bound and soluble protomeric alpha beta‐units of Na,K‐ATPase. Journal of Biological Chemistry 262: 10511–10517.

Voskoboinik I, Strausak D, Greenough M et al. (1999) Functional analysis of the N‐terminal CXXC metal‐binding motifs in the human Menkes copper‐transporting P‐type ATPase expressed in cultured mammalian cells. Journal of Biological Chemistry 274: 22008–22012.

Yatsunyk LA and Rosenzweig AC (2007) Cu(I) binding and transfer by the N terminus of the Wilson disease protein. Journal of Biological Chemistry 282: 8622–8631.

Further Reading

Hou Z and Mitra B (2003) The metal specificity and selectivity of ZntA from E. coli using the acylphosphate intermediate. Journal of Biological Chemistry 278: 28455–28461.

Zhang Z, Zheng Y, Mazon H et al. (2008) Structure of the yeast vacuolar ATPase. Journal of Biological Chemistry 283: 35983–35995.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Shin, Jai Moo, and Sachs, George(Sep 2009) Ion Motive ATPases: P‐type ATPases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001379.pub2]