ArticleProceedings of the National Academy of Sciences of the United States of America2012
Investigation of the sodium-binding sites in the sodium-coupled betaine transporter BetP.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 87 citations in OpenAlex.
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- Cryo-EM structure of the human NKCC1 transporter reveals mechanisms of ion coupling and specificity.The EMBO journal · 2022Article
- Pre-Training of Equivariant Graph Matching Networks with Conformation Flexibility for Drug Binding.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
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- Refining pairwise sequence alignments of membrane proteins by the incorporation of anchors.PloS one · 2021Article
- MemSTATS: A Benchmark Set of Membrane Protein Symmetries and Pseudosymmetries.Journal of molecular biology · 2020Article
- Functional Characterization of SLC Transporters Using Solid Supported Membranes.Methods in molecular biology (Clifton, N.J.) · 2020Article
- Locking Two Rigid-body Bundles in an Outward-Facing Conformation: The Ion-coupling Mechanism in a LeuT-fold Transporter.Scientific reports · 2019Article
- Unconventional transport of metal ions and protons by Nramps.The Journal of general physiology · 2019Article
- Serotonin transport in the 21st century.The Journal of general physiology · 2019Review
- Identification and characterization of a carnitine transporter in Acinetobacter baumannii.MicrobiologyOpen · 2019Article
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Authors and funding
7 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sodium-coupled substrate transport plays a central role in many biological processes. However, despite knowledge of the structures of several sodium-coupled transporters, the location of the sodium-binding site(s) often remains unclear. Several of these structures have the five transmembrane-helix inverted-topology repeat, LeuT-like (FIRL) fold, whose pseudosymmetry has been proposed to facilitate the alternating-access mechanism required for transport. Here, we provide biophysical, biochemical, and computational evidence for the location of the two cation-binding sites in the sodium-coupled betaine symporter BetP. A recent X-ray structure of BetP in a sodium-bound closed state revealed that one of these sites, equivalent to the Na2 site in related transporters, is located between transmembrane helices 1 and 8 of the FIRL-fold; here, we confirm the location of this site by other means. Based on the pseudosymmetry of this fold, we hypothesized that the second site is located between the equivalent helices 6 and 3. Molecular dynamics simulations of the closed-state structure suggest this second sodium site involves two threonine sidechains and a backbone carbonyl from helix 3, a phenylalanine from helix 6, and a water molecule. Mutating the residues proposed to form the two binding sites increased the apparent K(m) and K(d) for sodium, as measured by betaine uptake, tryptophan fluorescence, and (22)Na(+) binding, and also diminished the transient currents measured in proteoliposomes using solid supported membrane-based electrophysiology. Taken together, these results provide strong evidence for the identity of the residues forming the sodium-binding sites in BetP.
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