The molecular mechanism of regulation of the NhaA Na⁺/H⁺ antiporter of Escherichia coli, a key transporter in the adaptation to Na⁺ and H⁺

The NhaA Na⁺/H⁺ antiporter is the main system responsible for adaptation to Na⁺ and alkaline pH (in the presence of Na⁺) in Escherichia coli and many other enteric bacteria. It is under intricate control. At the protein level it is regulated directly by pH, one of its regulatory signals. A pH shift from 7 to 8.5 activates the antiporter and, in a fashion correlated with the activity change, confers a conformation change that, in isolated membrane vesicles, is reflected in the exposure of trypsin-cleavable sites. H225 and G338 are essential for the pH response of NhaA. nhaA transcription is dependent on NhaR, a positive regulator of the LysR family, and is regulated by Na⁺, the other environmental signal. Na⁺ affects the NhaR/nhaA interaction directly by changing the footprint of NhaR on nhaA in a pH-dependent fashion. The expression of nhaA is also under global regulation of H-NS. We suggest that the pattern of regulation of nhaA found in E. coli is a paradigm for the response of proteins and genes to H⁺ and Na⁺, the most common ions that challenge every cell.