The conserved glutamate (Glu136) in transmembrane domain 2 of the serotonin transporter is required for the conformational switch in the transport cycle.

The Journal of Biological Chemistry
Vladimir M KorkhovHarald H Sitte

Abstract

The alternate access model provides the theoretical framework for understanding how transporters translocate hydrophilic substrates across the lipid bilayer. The model postulates at least two conformations of a transporter, an outward and an inward facing conformation, which seal the translocation pathway to the interior and exterior of the cell, respectively. It is not clear how the conformational switch is triggered in neurotransmitter/sodium symporters, but Na+ is likely to play an essential role. Here, we focused on Glu136 of the serotonin transporter (SERT); this residue is conserved in transmembrane domain 2 of neurotransmitter/sodium symporters and related proteins. Three substitutions were introduced, resulting in SERT-E136D, SERT-E136Q, and SERT-E136A, which were all correctly inserted into the plasma membrane. SERT-E136Q and SERT-E136A failed to support substrate influx into cells, whereas SERT-E136D did so at a reduced rate. Binding experiments with the inhibitor 2beta-[3H]carbomethoxy-3beta-(4-iodophenyl)tropane (beta-[3H]CIT) supported the conjecture that the mutant transporters preferentially adopted the inward facing conformation: beta-[3H]CIT interacted with SERT in a manner consistent with binding to the outwar...Continue Reading

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Citations

Feb 2, 2010·The Journal of Biological Chemistry·Sonja SucicHarald H Sitte
Oct 29, 2011·The Journal of Biological Chemistry·Linda WildlingPeter Hinterdorfer
Mar 28, 2012·The Journal of Biological Chemistry·Simon BullingWalter Sandtner
Jul 27, 2007·Proceedings of the National Academy of Sciences of the United States of America·Lucy R ForrestBarry Honig
Nov 7, 2009·Journal of Neurochemistry·Harald H Sitte, Michael Freissmuth
May 28, 2013·Journal of Molecular Biology·Saba Abdul-HusseinChristopher G Tate
Feb 14, 2018·The Journal of General Physiology·Peter S HasenhuetlWalter Sandtner
Nov 15, 2017·International Journal of Molecular Sciences·H M Mazhar AsjadChristian Nanoff
Feb 7, 2008·The Journal of Biological Chemistry·Ingo BartholomäusVolker Eulenburg
Jan 26, 2008·The Journal of Biological Chemistry·Christoforos CharalambousJürgen Zezula
Jan 13, 2018·PLoS Computational Biology·Talia ZeppelinBirgit Schiøtt
Jan 21, 2017·The Journal of Biological Chemistry·Carina KernSonja Sucic

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