ArticleThe Journal of biological chemistry2012
A model-structure of a periplasm-facing state of the NhaA antiporter suggests the molecular underpinnings of pH-induced conformational changes.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 30 citations in OpenAlex.
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- Memorization Bias Impacts Modeling of Alternative Conformational States of Symmetric Solute Carrier Membrane Proteins with Methods from Deep Learning.bioRxiv : the preprint server for biology · 2025Article
- General principles of secondary active transporter function.Biophysics reviews · 2022Review
- An angular motion of a conserved four-helix bundle facilitates alternating access transport in the TtNapA and EcNhaA transporters.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Dynamics-function relationship in the catalytic domains of N-terminal acetyltransferases.Computational and structural biotechnology journal · 2020Article
- Critical Functions of Region 1-67 and Helix XIII in Retaining the Active Structure of NhaD Antiporter inFrontiers in microbiology · 2018Article
- Ligand-induced conformational dynamics of theProceedings of the National Academy of Sciences of the United States of America · 2017Article
- Lysine 300 is essential for stability but not for electrogenic transport of theThe Journal of biological chemistry · 2017Article
- The bacterial dicarboxylate transporter VcINDY uses a two-domain elevator-type mechanism.Nature structural & molecular biology · 2016Article
- NhaA antiporter functions using 10 helices, and an additional 2 contribute to assembly/stability.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Gating topology of the proton-coupled oligopeptide symporters.Structure (London, England : 1993) · 2015Article
- Structural Symmetry in Membrane Proteins.Annual review of biophysics · 2015Review
- Repeat-swap homology modeling of secondary active transporters: updated protocol and prediction of elevator-type mechanisms.Frontiers in pharmacology · 2015Article
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- Revealing the ligand binding site of NhaA Na+/H+ antiporter and its pH dependence.The Journal of biological chemistry · 2012Article
- A cationic lumen in the Wzx flippase mediates anionic O-antigen subunit translocation in Pseudomonas aeruginosa PAO1.Molecular microbiology · 2012Article
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Escherichia coli NhaA antiporter couples the transport of H(+) and Na(+) (or Li(+)) ions to maintain the proper pH range and Na(+) concentration in cells. A crystal structure of NhaA, solved at pH 4, comprises 12 transmembrane helices (TMs), arranged in two domains, with a large cytoplasm-facing funnel and a smaller periplasm-facing funnel. NhaA undergoes conformational changes, e.g. after pH elevation to alkaline ranges, and we used two computational approaches to explore them. On the basis of pseudo-symmetric features of the crystal structure, we predicted the structural architecture of an alternate, periplasm-facing state. In contrast to the crystal structure, the model presents a closed cytoplasmic funnel, and a periplasmic funnel of greater volume. To examine the transporter functional direction of motion, we conducted elastic network analysis of the crystal structure and detected two main normal modes of motion. Notably, both analyses predicted similar trends of conformational changes, consisting of an overall rotational motion of the two domains around a putative symmetry axis at the funnel centers, perpendicular to the membrane plane. This motion, along with conformational changes within specific helices, resulted in closure at the cytoplasmic end and opening at the periplasmic end. Cross-linking experiments, performed between segments on opposite sides of the cytoplasmic funnel, revealed pH-dependent interactions consistent with the proposed conformational changes. We suggest that the model-structure and predicted motion represent alkaline pH-induced conformational changes, mediated by a cluster of evolutionarily conserved, titratable residues, at the cytoplasmic ends of TMs II, V, and IX.
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