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Papers In Press, published online ahead of print October 31, 2000
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510
Corresponding Author: megan.stephan{at}yale.edu
Mutations at critical residue positions in transmembrane span 7 (TM7) of the serotonin transporter affect the Na+ dependence of transport. It was possible that these residues, which form a stripe along one side of the predicted alpha helix, formed part of a water-filled pore for Na+. We tested whether cysteine substitutions in TM7 were accessible to hydrophilic, membrane-impermeant methanethiosulfonate (MTS) reagents. Although all five cysteine-containing mutants tested were sensitive to these reagents, non-cysteine control mutants at the same positions were in most cases equally sensitive. In all cases, MTS sensitivity could be traced to changes in accessibility of a native cysteine residue in extracellular loop 1, Cys-109. Moreover, none of the TM7 cysteines reacted with the biotinylating reagent MTSEA-biotin when tested in the C109A background. It is thus unlikely that the critical stripe forms part of a water-filled pore. Instead, studies of the ion dependence of the reaction between Cys-109 and MTS reagents lead to the conclusion that TM7 is involved in propagating conformational changes caused by ion binding, perhaps as part of the translocation mechanism. The critical stripe residues on TM7 probably represent a close contact region between TM7 and one or more other TM's in the transporter's three-dimensional structure.
J. Biol. Chem, 10.1074/jbc.M008483200
Submitted on September 15, 2000
Revised on October 31, 2000
Accepted on October 31, 2000
Functional role of critical stripe residues in transmembrane span 7 of the serotonin transporter: effects of Na+, Li+ and methanethiosulfonate reagents
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