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.
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, 161–163.10.1038/299161a0Search 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, 485–494.10.1097/01.mnh.0000174146.52915.5dSearch 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–C239.10.1152/ajpcell.00360.2004Search 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, 3111–3116.10.1016/j.febslet.2014.05.066Search 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, 13168–13176.10.1074/jbc.M113.542993Search 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, 236–251.10.1016/j.mam.2012.05.001Search 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, 439–449.10.1038/emboj.2010.321Search 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, 1197–1202.10.1038/nature03692Search in Google Scholar
Jardetzky, O. (1966). Simple allosteric model for membrane pumps. Nature 211, 969–970.10.1038/211969a0Search 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, 161–164.10.1016/0005-2736(82)90200-0Search 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, 279–288.10.1111/j.1749-6632.1985.tb14877.xSearch in Google Scholar PubMed
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, 330–343.10.1038/nrmicro2549Search in Google Scholar PubMed PubMed Central
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, 37854–37863.10.1074/jbc.M705460200Search in Google Scholar PubMed
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, 573–577.10.1038/nature12484Search in Google Scholar PubMed PubMed Central
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, 529–544.10.1085/jgp.201411219Search in Google Scholar PubMed PubMed Central
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, e101575.10.1371/journal.pone.0101575Search in Google Scholar PubMed PubMed Central
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, 23570–23581.10.1074/jbc.M111.230235Search in Google Scholar PubMed PubMed Central
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, 443–450.10.1021/bi101082eSearch in Google Scholar PubMed
Padan, E., Bibi, E., Ito, M., and Krulwich, T.A. (2005). Alkaline pH homeostasis in bacteria: new insights. Biochim. Biophys. Acta 1717, 67–88.10.1016/j.bbamem.2005.09.010Search in Google Scholar PubMed PubMed Central
Padan, E., Kozachkov, L., Herz, K., and Rimon, A. (2009). NhaA crystal structure: functional-structural insights. J. Exp. Biol. 212, 1593–1603.10.1242/jeb.026708Search in Google Scholar PubMed
Paulino, C. and Kuhlbrandt, W. (2014). pH- and sodium-induced changes in a sodium/proton antiporter. eLife 3, e01412.10.7554/eLife.01412Search in Google Scholar PubMed PubMed Central
Paulino, C., Wohlert, D., Kapotova, E., Yildiz, O., and Kuhlbrandt, W. (2014). Structure and transport mechanism of the sodium/ proton antiporter MjNhaP1. eLife 3, e03583.10.7554/eLife.03583.029Search in Google Scholar
Stein, W.D. and Honig, B. (1977). Models for active-transport of cations-steady-state analysis. Mol. Cell. Biochem. 15, 27–44.10.1007/BF01731287Search in Google Scholar PubMed
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, 579–591.10.1038/nrmicro1931Search in Google Scholar PubMed
Wohlert, D., Yildiz, O., and Kuhlbrandt, W. (2014). Structure and substrate ion binding in the sodium/proton antiporter PaNhaP. eLife 3, e03579.10.7554/eLife.03579.026Search in Google Scholar
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