Mechanism of pH-dependent activation of the sodium-proton antiporter NhaA

Yandong Huang, Wei Chen, David L. Dotson, Oliver Beckstein and Jana Shen ()
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Yandong Huang: University of Maryland School of Pharmacy
Wei Chen: University of Maryland School of Pharmacy
David L. Dotson: Arizona State University
Oliver Beckstein: Arizona State University
Jana Shen: University of Maryland School of Pharmacy

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract Escherichia coli NhaA is a prototype sodium-proton antiporter, which has been extensively characterized by X-ray crystallography, biochemical and biophysical experiments. However, the identities of proton carriers and details of pH-regulated mechanism remain controversial. Here we report constant pH molecular dynamics data, which reveal that NhaA activation involves a net charge switch of a pH sensor at the entrance of the cytoplasmic funnel and opening of a hydrophobic gate at the end of the funnel. The latter is triggered by charging of Asp164, the first proton carrier. The second proton carrier Lys300 forms a salt bridge with Asp163 in the inactive state, and releases a proton when a sodium ion binds Asp163. These data reconcile current models and illustrate the power of state-of-the-art molecular dynamics simulations in providing atomic details of proton-coupled transport across membrane which is challenging to elucidate by experimental techniques.

Date: 2016
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DOI: 10.1038/ncomms12940

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