Regulation of NhaAby Protons

Abstract

H(+), a most common ion, is involved in very many biological processes. However, most proteins have distinct ranges of pH for function; when the H(+) concentration in the cells is too high or too low, protons turn into very potent stressors to all cells. Therefore, all living cells are strictly dependent on homeostasis mechanisms that regulate their intracellular pH. Na(+)/H(+) antiporters play primary role in pH homeostatic mechanisms both in prokaryotes and eukaryotes. Regulation by pH is a property common to these antiporters. They are equipped with a pH sensor to perceive the pH signal and a pH transducer to transduce the signal into a change in activity. Determining the crystal structure of NhaA, the Na(+)/H(+) antiporter of Escherichia coli have provided the basis for understanding in a realistic rational way the unique regulation of an antiporter by pH and the mechanism of the antiport activity. The physical separation between the pH sensor/transducer and the active site revealed by the structure entailed long-range pH-induced conformational changes for NhaA pH activation. As yet, it is not possible to decide whether the amino acid participating in the pH sensor and the pH transducer overlap or are separated. The pH sensor/transducer is not a single amino acid but rather a cluster of electrostatically interacting residues. Thus, integrating structural, computational, and experimental approaches are essential to reveal how the pH signal is perceived and transduced to activate the pH regulated protein.