A universal mechanism for transport and regulation of CPA sodium proton exchangers

Octavian Călinescu and Klaus Fendler 1
  • 1 Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, D-60438 Frankfurt/Main, Germany
  • 2 Department of Biophysics, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, RO-050474 Bucharest, Romania
Octavian Călinescu and Klaus Fendler

Abstract

Recent studies performed on a series of Na+/H+ exchangers have led us to postulate a general mechanism for Na+/H+ exchange in the monovalent cation/proton antiporter superfamily. This simple mechanism employs a single binding site for which both substrates compete. The developed kinetic model is self-regulatory, ensuring down-regulation of transport activity at extreme pH, and elegantly explains the pH-dependent activity of Na+/H+ exchangers. The mechanism was experimentally verified and shown to describe both electrogenic and electroneutral exchangers. Using a small number of parameters, exchanger activity can be modeled under different conditions, providing insights into the physiological role of Na+/H+ exchangers.

  • Aronson, P.S., Nee, J., and Suhm, M.A. (1982). Modifier role of internal H+ in activating the Na+-H+ exchanger in renal microvillus membrane vesicles. Nature 299, 161–163.

  • Bobulescu, I.A., Di Sole, F., and Moe, O.W. (2005). Na+/H+ exchangers: physiology and link to hypertension and organ ischemia. Curr. Opin. Nephrol. Hypertens. 14, 485–494.

  • Brett, C.L., Donowitz, M., and Rao, R. (2005). Evolutionary origins of eukaryotic sodium/proton exchangers. Am. J. Physiol. Cell Physiol. 288, C223–C239.

  • Calinescu, O., Danner, E., Bohm, M., Hunte, C., and Fendler, K. (2014a). Species differences in bacterial NhaA Na+/H+ exchangers. FEBS Lett. 588, 3111–3116.

  • Calinescu, O., Paulino, C., Kuhlbrandt, W., and Fendler, K. (2014b). Keeping it simple, transport mechanism and pH regulation in Na+/H+ exchangers. J. Biol. Chem. 289, 13168–13176.

  • Donowitz, M., Ming Tse, C., and Fuster, D. (2013). SLC9/NHE gene family, a plasma membrane and organellar family of Na+/H+ exchangers. Mol. Aspects Med. 34, 236–251.

  • Goswami, P., Paulino, C., Hizlan, D., Vonck, J., Yildiz, O., and Kuhlbrandt, W. (2011). Structure of the archaeal Na+/H+ antiporter NhaP1 and functional role of transmembrane helix 1. EMBO J. 30, 439–449.

  • Hunte, C., Screpanti, E., Venturi, M., Rimon, A., Padan, E., and Michel, H. (2005). Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH. Nature 435, 1197–1202.

  • Jardetzky, O. (1966). Simple allosteric model for membrane pumps. Nature 211, 969–970.

  • Kinsella, J.L. and Aronson, P.S. (1982). Determination of the coupling ratio for Na+ -H+ exchange in renal microvillus membrane vesicles. Biochim. Biophys. Acta 689, 161–164.

  • Klingenberg, M. (1985a). Catalytic energy and carrier-catalyzed solute transport in biomembranes. In: Achievements and Perspectives of Mitochondrial Research, Vol. I, Bioenergetics, E. Quagliariello, E.C. Slater, F. Palmieri, C. Saccone, and A.M. Kroon, eds. (Amsterdam, New York, Oxford: Elsevier Science Publisher).

  • Klingenberg, M. (1985b). Principles of carrier catalysis elucidated by comparing two similar membrane translocators from mitochondria, the ADP/ATP carrier and the uncoupling protein. Ann. N.Y. Acad. Sci. 456, 279–288.

  • Klingenberg, M. (1992). Mechanistic and energetic aspects of carrier catalysis-exemplified with mitochondrial translocators. In: A Study of Enzymes, S.A. Kuby, ed. (Boca Raton, Ann Arbor, Boston: CRC Press).

  • Krulwich, T.A., Sachs, G., and Padan, E. (2011). Molecular aspects of bacterial pH sensing and homeostasis. Nat. Rev. Microbiol. 9, 330–343.

  • Landau, M., Herz, K., Padan, E., and Ben-Tal, N. (2007). Model structure of the Na+/H+ exchanger 1 (NHE1): functional and clinical implications. J. Biol. Chem. 282, 37854–37863.

  • Leblanc, G., Bassilana, M., and Damiano-Forano, E. (1988). Na+/H+ exchange in bacteria and organelles. In: Na+/H+ Exchange, S. Grinstein and D. Piwnica-Worms, eds. (Boca Raton, Florida: CRC Press).

  • Lee, C., Kang, H.J., Von Ballmoos, C., Newstead, S., Uzdavinys, P., Dotson, D.L., Iwata, S., Beckstein, O., Cameron, A.D., and Drew, D. (2013). A two-domain elevator mechanism for sodium/proton antiport. Nature 501, 573–577.

  • Lee, C., Yashiro, S., Dotson, D.L., Uzdavinys, P., Iwata, S., Sansom, M.S., Von Ballmoos, C., Beckstein, O., Drew, D., and Cameron, A.D. (2014). Crystal structure of the sodium-proton antiporter NhaA dimer and new mechanistic insights. J. Gen. Physiol. 144, 529–544.

  • Lentes, C.J., Mir, S.H., Boehm, M., Ganea, C., Fendler, K., and Hunte, C. (2014). Molecular characterization of the Na+/H+-antiporter NhaA from Salmonella typhimurium. PLoS One 9, e101575.

  • Mager, T., Rimon, A., Padan, E., and Fendler, K. (2011). Transport mechanism and pH regulation of the Na+/H+ antiporter NhaA from Escherichia coli: an electrophysiological study. J. Biol. Chem. 286, 23570–23581.

  • Ohgaki, R., Van, I.S.C., Matsushita, M., Hoekstra, D., and Kanazawa, H. (2011). Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50, 443–450.

  • Padan, E., Bibi, E., Ito, M., and Krulwich, T.A. (2005). Alkaline pH homeostasis in bacteria: new insights. Biochim. Biophys. Acta 1717, 67–88.

  • Padan, E., Kozachkov, L., Herz, K., and Rimon, A. (2009). NhaA crystal structure: functional-structural insights. J. Exp. Biol. 212, 1593–1603.

  • Paulino, C. and Kuhlbrandt, W. (2014). pH- and sodium-induced changes in a sodium/proton antiporter. eLife 3, e01412.

  • Paulino, C., Wohlert, D., Kapotova, E., Yildiz, O., and Kuhlbrandt, W. (2014). Structure and transport mechanism of the sodium/ proton antiporter MjNhaP1. eLife 3, e03583.

  • Stein, W.D. and Honig, B. (1977). Models for active-transport of cations-steady-state analysis. Mol. Cell. Biochem. 15, 27–44.

  • Thauer, R.K., Kaster, A.K., Seedorf, H., Buckel, W., and Hedderich, R. (2008). Methanogenic archaea: ecologically relevant differences in energy conservation. Nat. Rev. Microbiol. 6, 579–591.

  • Wohlert, D., Yildiz, O., and Kuhlbrandt, W. (2014). Structure and substrate ion binding in the sodium/proton antiporter PaNhaP. eLife 3, e03579.

Purchase article
Get instant unlimited access to the article.
$42.00
Log in
Already have access? Please log in.


or
Log in with your institution

Journal + Issues

Biological Chemistry keeps you up-to-date with the latest advances in the molecular life sciences. The journal publishes Research Articles, Short Communications, Reviews and Minireviews. Areas include: general biochemistry/pathobiochemistry, structural biology, molecular and cellular biology, genetics and epigenetics, virology, molecular medicine, plant molecular biology/biochemistry and novel experimental methodologies.

Search