Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 31, Pages 12761-12766Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0705600104
Keywords
neurotransmitters; neurotransmitter : sodium symporters; serotonin; homology modeling; pK(A) calculation
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Funding
- NIDA NIH HHS [DA 007295, T32 DA007295, R01 DA008213] Funding Source: Medline
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The recent determination of the crystal structure of the leucine transporter from Aquifex aeolicus (aaLeuT) has provided significant insights into the function of neurotransmitter:sodium symporters. Transport by aaLeuT is Cl- independent, whereas many neurotransmitter:sodium symporters from higher organisms depend on Cl- ions. However, the only Cl- ion identified in the aaLeuT structure interacts with nonconserved residues in extracellular loops, and thus the relevance of this binding site is unclear. Here, we use calculations of pK(A)s and homology modeling to predict the location of a functionally important Cl- binding site in serotonin transporter and other Cl--dependent transporters. We validate our model through the site-directed mutagenesis of residues predicted to coordinate the Cl-ion and through the observation of sequence conservation patterns in other Cl--dependent transporters. The proposed site is located midway across the membrane and is formed by residues from transmembrane helices 2, 6, and 7. It is close to the Na1 sodium binding site, thus providing an explanation for the coupling of Cl- and Na+ ions during transport. Other implications of the model are also discussed.
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