Accessible Requires Authentication Published by De Gruyter January 28, 2015

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

Octavian Călinescu and Klaus Fendler
From the journal Biological Chemistry

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.


Corresponding author: Klaus Fendler, Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, D-60438 Frankfurt/Main, Germany, e-mail:

References

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. Search in Google Scholar

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. Search in Google Scholar

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

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. Search in Google Scholar

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. Search in Google Scholar

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. Search in Google Scholar

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. Search in Google Scholar

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. Search in Google Scholar

Jardetzky, O. (1966). Simple allosteric model for membrane pumps. Nature 211, 969–970. Search in Google Scholar

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. Search in Google Scholar

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). Search in Google Scholar

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. Search in Google Scholar

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). Search in Google Scholar

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

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. Search in Google Scholar

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). Search in Google Scholar

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. Search in Google Scholar

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. Search in Google Scholar

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. Search in Google Scholar

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. Search in Google Scholar

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. Search in Google Scholar

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

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

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

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. Search in Google Scholar

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

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. Search in Google Scholar

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

Received: 2014-11-28
Accepted: 2015-1-26
Published Online: 2015-1-28
Published in Print: 2015-9-1

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