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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kuhlmann, Sonja I. Faraldo-gómez, José D. Ziegler, Christine Kunte, Hans-jörg Marinelli, Fabrizio Grell, Ernst |
| Description | Author Affiliation: Marinelli F ( Theoretical Molecular Biophysics Group, Max Planck Institute of Biophysics, Frankfurt am Main, Germany.); |
| Abstract | Numerous membrane importers rely on accessory water-soluble proteins to capture their substrates. These substrate-binding proteins (SBP) have a strong affinity for their ligands; yet, substrate release onto the low-affinity membrane transporter must occur for uptake to proceed. It is generally accepted that release is facilitated by the association of SBP and transporter, upon which the SBP adopts a conformation similar to the unliganded state, whose affinity is sufficiently reduced. Despite the appeal of this mechanism, however, direct supporting evidence is lacking. Here, we use experimental and theoretical methods to demonstrate that an allosteric mechanism of enhanced substrate release is indeed plausible. First, we report the atomic-resolution structure of apo TeaA, the SBP of the Na(+)-coupled ectoine TRAP transporter TeaBC from Halomonas elongata DSM2581(T), and compare it with the substrate-bound structure previously reported. Conformational free-energy landscape calculations based upon molecular dynamics simulations are then used to dissect the mechanism that couples ectoine binding to structural change in TeaA. These insights allow us to design a triple mutation that biases TeaA toward apo-like conformations without directly perturbing the binding cleft, thus mimicking the influence of the membrane transporter. Calorimetric measurements demonstrate that the ectoine affinity of the conformationally biased triple mutant is 100-fold weaker than that of the wild type. By contrast, a control mutant predicted to be conformationally unbiased displays wild-type affinity. This work thus demonstrates that substrate release from SBPs onto their membrane transporters can be facilitated by the latter through a mechanism of allosteric modulation of the former. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 49 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Bacterial Proteins Chemistry Membrane Transport Proteins Protein Conformation Protein Structure, Tertiary Amino Acid Substitution Amino Acids, Diamino Metabolism Genetics Binding Sites Binding, Competitive Calorimetry Crystallography, X-Ray Halomonas Models, Molecular Mutation Protein Binding Thermodynamics Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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