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First published online May 15, 2009
Journal of Experimental Biology 212, 1593-1603 (2009)
Published by The Company of Biologists 2009
doi: 10.1242/jeb.026708

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Review Article

NhaA crystal structure: functional–structural insights

Etana Padan^*, Lena Kozachkov, Katia Herz and Abraham Rimon

Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel

^* Author for correspondence (e-mail: etana{at}vms.huji.ac.il)

Accepted 19 November 2008

Na⁺/H⁺ antiporters are integral membrane proteins that exchange Na⁺ for H⁺ across the cytoplasmic membrane and many intracellular membranes. They are essential for Na⁺, pH and volume homeostasis, which are crucial processes for cell viability. Accordingly, antiporters are important drug targets in humans and underlie salt-resistance in plants. Many Na⁺/H⁺ antiporters are tightly regulated by pH. Escherichia coli NhaA Na⁺/H⁺ antiporter, a prototype pH-regulated antiporter, exchanges 2 H⁺ for 1 Na⁺ (or Li⁺). The NhaA crystal structure has provided insights into the pH-regulated mechanism of antiporter action and opened up new in silico and in situ avenues of research. The monomer is the functional unit of NhaA yet the dimer is essential for the stability of the antiporter under extreme stress conditions. Ionizable residues of NhaA that strongly interact electrostatically are organized in a transmembrane fashion in accordance with the functional organization of the cation-binding site, `pH sensor', the pH transduction pathway and the pH-induced conformational changes. Remarkably, NhaA contains an inverted topology motive of transmembrane segments, which are interrupted by extended mid-membrane chains that have since been found to vary in other ion-transport proteins. This novel structural fold creates a delicately balanced electrostatic environment in the middle of the membrane, which might be essential for ion binding and translocation. Based on the crystal structure of NhaA, a model structure of the human Na⁺/H⁺ exchanger (NHE1) was constructed, paving the way to a rational drug design.

Key words: NhaA, NHA, NHE, Na⁺/H⁺ antiporters, active transport, membrane proteins

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