Crystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing. Winkelmann, I., Uzdavinys, P., Kenney, I. M., Brock, J., Meier, P. F., Wagner, L., Gabriel, F., Jung, S., Matsuoka, R., von Ballmoos, C., Beckstein, O., & Drew, D. Nature Communications, 13(1):6383, October, 2022. Number: 1 Publisher: Nature Publishing Group
Crystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing [link]Paper  doi  abstract   bibtex   2 downloads  
The strict exchange of protons for sodium ions across cell membranes by Na+/H+ exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na+/H+ exchange can be modelled as competition between H+ and Na+ to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na+/H+ antiporter NhaA from Escherichia coli, has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active. It was unclear how to incorporate the pH senor model into an alternating-access mechanism based on the NhaA structure at inactive pH 4. Here, we report the crystal structure of NhaA at active pH 6.5, and to an improved resolution of 2.2 Å. We show that at pH 6.5, residues in the pH sensor rearrange to form new salt-bridge interactions involving key histidine residues that widen the inward-facing cavity. What we now refer to as a pH gate, triggers a conformational change that enables water and Na+ to access the ion-binding site, as supported by molecular dynamics (MD) simulations. Our work highlights a unique, channel-like switch prior to substrate translocation in a secondary-active transporter.
@article{winkelmann_crystal_2022,
	title = {Crystal structure of the {Na}+/{H}+ antiporter {NhaA} at active {pH} reveals the mechanistic basis for {pH} sensing},
	volume = {13},
	copyright = {2022 The Author(s)},
	issn = {2041-1723},
	url = {https://www.nature.com/articles/s41467-022-34120-z},
	doi = {10.1038/s41467-022-34120-z},
	abstract = {The strict exchange of protons for sodium ions across cell membranes by Na+/H+ exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na+/H+ exchange can be modelled as competition between H+ and Na+ to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na+/H+ antiporter NhaA from Escherichia coli, has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active. It was unclear how to incorporate the pH senor model into an alternating-access mechanism based on the NhaA structure at inactive pH 4. Here, we report the crystal structure of NhaA at active pH 6.5, and to an improved resolution of 2.2 Å. We show that at pH 6.5, residues in the pH sensor rearrange to form new salt-bridge interactions involving key histidine residues that widen the inward-facing cavity. What we now refer to as a pH gate, triggers a conformational change that enables water and Na+ to access the ion-binding site, as supported by molecular dynamics (MD) simulations. Our work highlights a unique, channel-like switch prior to substrate translocation in a secondary-active transporter.},
	language = {en},
	number = {1},
	urldate = {2022-12-13},
	journal = {Nature Communications},
	author = {Winkelmann, Iven and Uzdavinys, Povilas and Kenney, Ian M. and Brock, Joseph and Meier, Pascal F. and Wagner, Lina-Marie and Gabriel, Florian and Jung, Sukkyeong and Matsuoka, Rei and von Ballmoos, Christoph and Beckstein, Oliver and Drew, David},
	month = oct,
	year = {2022},
	note = {Number: 1
Publisher: Nature Publishing Group},
	keywords = {Bioenergetics, Membrane proteins, Membrane structure and assembly, X-ray crystallography},
	pages = {6383},
}
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