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  Combined computational and biochemical study reveals the importance of electrostatic interactions between the ‘‘pH sensor’’ and the cation binding site of the sodium/proton antiporter NhaA of Escherichia coli

Olkhova, E., Kozachkov, L., Padan, E., & Michel, H. (2009). Combined computational and biochemical study reveals the importance of electrostatic interactions between the ‘‘pH sensor’’ and the cation binding site of the sodium/proton antiporter NhaA of Escherichia coli. Proteins: Structure, Function, and Bioinformatics, 76(3), 548-559.

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Datensatz-Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-D7D0-2 Versions-Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-D7D2-D
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 Urheber:
Olkhova, Elena1, Autor              
Kozachkov, Lena, Autor
Padan, Etana, Autor
Michel, Hartmut1, Autor              
Affiliations:
1Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society, ou_2068290              

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Schlagwörter: NhaA Na+/H+ antiporter; conformation; single mutations; pH-dependent activation; continuum electrostatics
 Zusammenfassung: Sodium proton antiporters are essential enzymes that catalyze the exchange of sodium ions for protons across biological membranes. The crystal structure of NhaA has provided a basis to explore the mechanism of ion exchange and it's unique regulation by pH. Here, the mechanism of the pH activation of the antiporter is investigated through functional and computational studies of several variants with mutations in the ion-binding site (D163, D164). The most significant difference found computationally between the wild type antiporter and the active site variants, D163E and D164N, are low pKa values of Glu78 making them insensitive to pH. Although in the variant D163N the pKa of Glu78 is comparable to the physiological one, this variant cannot demonstrate the long-range electrostatic effect of Glu78 on the pH-dependent structural reorganization of trans-membrane helix X and, hence, is proposed to be inactive. In marked contrast, variant D164E remains sensitive to pH and can be activated by alkaline pH shift. Remarkably, as expected computationally and discovered here biochemically, D164E is viable and active in Na+/H+ exchange albeit with increased apparent KM. Our results unravel the unique electrostatic network of NhaA that connect the coupled clusters of the ‘‘pH sensor’’ with the binding site, which is crucial for pH activation of NhaA

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Sprache(n): eng - Englisch
 Datum: 2009
 Publikationsstatus: Im Druck veröffentlicht
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: eDoc: 473576
 Art des Abschluß: -

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Titel: Proteins: Structure, Function, and Bioinformatics
  Alternativer Titel : Proteins: Struct., Funct., Bioinf.
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 76 (3) Artikelnummer: - Start- / Endseite: 548 - 559 Identifikator: -