Physiological, Structural, and Functional Analysis of the Paralogous Cation-Proton Antiporters of NhaP Type from Vibrio cholerae

The transmembrane K /H antiporters of NhaP type of (Vc-NhaP1, 2, and 3) are critical for maintenance of K homeostasis in the cytoplasm. The entire functional NhaP group is indispensable for the survival of at low pHs suggesting their possible role in the acid tolerance response (ATR) of . Our findings suggest that the Vc-NhaP123 group, and especially its major component, Vc-NhaP2, might be a promising target for the development of novel antimicrobials by narrowly targeting and other NhaP-expressing pathogens. On the basis of Vc-NhaP2 in silico structure modeling, Molecular Dynamics Simulations, and extensive mutagenesis studies, we suggest that the ion-motive module of Vc-NhaP2 is comprised of two functional regions: (i) a putative cation-binding pocket that is formed by antiparallel unfolded regions of two transmembrane segments (TMSs V/XII) crossing each other in the middle of the membrane, known as the NhaA fold; and (ii) a cluster of amino acids determining the ion selectivity.