Abstract
The transmembrane K+/H+ antiporters of NhaP type of Vibrio cholerae (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 V. cholerae at low pHs suggesting their possible role in the acid tolerance response (ATR) of V. cholerae. 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 V. cholerae 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.
Highlights
Vibrio cholerae encodes for an elaborate set of membrane cation–proton antiporters that are responsible for the circulation of alkali cations Na+ and K+ [1,2]
We found that all three Vc-NhaP-type antiporters exchange K+ for H+ in vivo and operate in concert to maintain the viability of V. cholerae cells in acidic, especially K+-rich environments [5]
We found that a cluster of negatively charged and polar residues belonging to transmembrane segments (TMSs) V and VI of Vc-NhaP2 form the cation-binding pocket in the middle of the membrane [24]
Summary
Vibrio cholerae encodes for an elaborate set of membrane cation–proton antiporters that are responsible for the circulation of alkali cations Na+ and K+ [1,2]. The human homolog of NhaP type antiporters, the NHE1 Na+/H+ exchangers, have been shown to be associated with different diseases, and a change in the activity of NHE1 plays role in heart failure [6]. Comparison of the biochemical properties of Vc-NhaP isoforms revealed that Vc-NhaP2 is the most active among all three paralogues with apparent Km values for both K+ and Na+ of 1.6 and 1.04 mM respectively, whereas Vc-NhaP1 and Vc-NhaP3 demonstrated much weaker affinity to Na+ as well as K+ [3,5,23] To explain these experimental data, we have suggested that protons, as well as alkali cations, all compete for different subsets of ligands within the common spacious ion-binding site of Vc-NhaP2 [4]. Sci. 2019, 20, 2572 structural analysis would illuminate the intra-molecular events comprising the catalytic cycle of NhaP-type antiporters
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